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  • 1.
    Agathangelidis, Andreas
    et al.
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Gounari, Maria
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy;Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stamatopoulos, Kostas
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Tonon, Giovanni
    IRCCS Ist Sci San Raffaele, Funct Genom Canc Unit, Div Expt Oncol, Milan, Italy.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 5, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per-formed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lym phocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

  • 2.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Walz, Martin K.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Bioinformatic Challenges in Clinical Diagnostic Application of Targeted Next Generation Sequencing: Experience from Pheochromocytoma2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133210Article in journal (Refereed)
    Abstract [en]

    Background Recent studies have demonstrated equal quality of targeted next generation sequencing (NGS) compared to Sanger Sequencing. Whereas these novel sequencing processes have a validated robust performance, choice of enrichment method and different available bioinformatic software as reliable analysis tool needs to be further investigated in a diagnostic setting. Methods DNA from 21 patients with genetic variants in SDHB, VHL, EPAS1, RET, (n=17) or clinical criteria of NF1 syndrome (n=4) were included. Targeted NGS was performed using Truseq custom amplicon enrichment sequenced on an Illumina MiSEQ instrument. Results were analysed in parallel using three different bioinformatics pipelines; (1) Commercially available MiSEQ Reporter, fully automatized and integrated software, (2) CLC Genomics Workbench, graphical interface based software, also commercially available, and ICP (3) an in-house scripted custom bioinformatic tool. Results A tenfold read coverage was achieved in between 95-98% of targeted bases. All workflows had alignment of reads to SDHA and NF1 pseudogenes. Compared to Sanger sequencing, variant calling revealed a sensitivity ranging from 83 to 100% and a specificity of 99.9-100%. Only MiSEQ reporter identified all pathogenic variants in both sequencing runs. Conclusions We conclude that targeted next generation sequencing have equal quality compared to Sanger sequencing. Enrichment specificity and the bioinformatic performance need to be carefully assessed in a diagnostic setting. As acceptable accuracy was noted for a fully automated bioinformatic workflow, we suggest that processing of NGS data could be performed without expert bioinformatics skills utilizing already existing commercially available bioinformatics tools.

  • 3.
    Karimi, M.
    et al.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hansen, J. Werner
    Bartholin Inst, Dept Hematol, Copenhagen, Denmark..
    Kittang, A. Olsnes
    Haukeland Hosp, Dept Med, Bergen, Norway..
    Holm, M. Skov
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Dybedal, I.
    Oslo Univ Hosp, Dept Hematol, Oslo, Norway..
    Nograad, J. Maxwell
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Ebeling, F.
    Univ Helsinki, Cent Hosp, Dept Hematol, Helsinki, Finland..
    Walldin, G.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden..
    Jadersten, M.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden..
    Ladenvall, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gronbaek, K.
    Bartholin Inst, Dept Hematol, Copenhagen, Denmark..
    Hellström-Lindberg, E.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden..
    Molecular Profiling In A Population Based Cohort Of Nordic Myelodysplastic Syndrome Patients2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 72-72Article in journal (Other academic)
  • 4.
    Kiflemariam, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tumor Vessel Up-Regulation of INSR Revealed by Single-Cell Expression Analysis of the Tyrosine Kinome and Phosphatome in Human Cancers2015In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 6, p. 1600-1609Article in journal (Refereed)
    Abstract [en]

    The tyrosine kinome and phosphatome harbor oncogenes and tumor suppressor genes and important regulators of angiogenesis and tumor stroma formation. To provide a better understanding of their potential roles in cancer, we analyzed the expression of 85 tyrosine kinases and 42 tyrosine phosphatases by in situ hybridization 48 human normal and 24 tumor tissue specimens. Nine-tenths of the assessed transcripts had tumor cell expression concordant with expression array databases. Further, pan-cancer expression of AATK, PTPRK, and PTPRU and expression of PTPRS in a subset of tumors were observed. To demonstrate tumor subcompartment resolution, we validated the predicted tumor stroma-specific markers HTRA1, HTRA3, MXRA5, MXRA8, and SERPING1 in situ. In addition to known vascular and stromal markers such as PDGERB, we observed stromal expression of PTK6 and TNS1 and vascular expression of INSR, PTPRF, PTPRG, PTPRU, and TNS1, of which INSR emerged as a tumor-specific vessel marker. This study demonstrates the feasibility of Large-scale analyses to chart the transcriptome in situ in human cancers and their ability to identify novel cancer biomarkers.

  • 5.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Exploring next-generation sequencing in chronic lymphocytic leukemia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Next-generation sequencing (NGS) techniques have led to major breakthroughs in the characterization of the chronic lymphocytic leukemia (CLL) genome with discovery of recurrent mutations of potential prognostic and/or predictive relevance. However, before NGS can be introduced into clinical practice, the precision of the techniques needs to be studied in better detail. Furthermore, much remains unknown about the genetic mechanisms leading to aggressive disease and resistance to treatment. Hence, in Paper I, the technical performance of a targeted deep sequencing panel including 9 genes was evaluated in 188 CLL patients. We were able to validate 143/155 (92%) selected mutations through Sanger sequencing and 77/82 mutations were concordant in a second targeted sequencing run, indicating that the technique can be introduced in clinical practice. In Paper II we screened 18 NF-κB pathway genes in 315 CLL patients through targeted deep sequencing which revealed a recurrent 4 base-pair deletion in the NFKBIE gene. Screening of NFKBIE in 377 additional cases identified the mutation in ~6% of all CLL patients. We demonstrate that the lesion lead to aberrant NF-κB signaling through impaired interaction with p65 and is associated with unfavorable clinical outcome. In Paper III we sought to delineate the genetic lesions that leads to relapse after fludarabine, cyclophosphamide, and rituximab treatment. Through whole-exome sequencing of pre-treatment and relapse samples from 41 cases we found evidence of frequent selection of subclones harboring driver mutations and subsequent clonal evolution following treatment. We also detected mutations in the ribosomal protein RPS15 in 8 cases (19.5%) and characterization of the mutations through functional assays point to impaired p53 regulation in cells with mutated RPS15. Paper IV aimed at characterizing 70 patients assigned to three major subsets (#1, #2, and #4) through whole-genome sequencing. Besides recurrent exonic driver mutations, we report non-coding regions significantly enriched for mutations in subset #1 and #2 that may facilitate future molecular studies. Collectively, this thesis supports the potential of targeted sequencing for mutational screening of CLL in clinical practice, provides novel insight into the pathobiology of aggressive CLL, and demonstrates the clinical outcome and cellular effects of NFKBIE and RPS15 mutations. 

    List of papers
    1. Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting
    Open this publication in new window or tab >>Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting
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    2015 (English)In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, no 3, p. 370-376Article in journal (Refereed) Published
    Abstract [en]

    Next- generation sequencing has revealed novel recurrent mutations in chronic lymphocytic leukemia, particularly in patients with aggressive disease. Here, we explored targeted re- sequencing as a novel strategy to assess the mutation status of genes with prognostic potential. To this end, we utilized HaloPlex targeted enrichment technology and designed a panel including nine genes: ATM, BIRC3, MYD88, NOTCH1, SF3B1 and TP53, which have been linked to the prognosis of chronic lymphocytic leukemia, and KLHL6, POT1 and XPO1, which are less characterized but were found to be recurrently mutated in various sequencing studies. A total of 188 chronic lymphocytic leukemia patients with poor prognostic features ( unmutated IGHV, n= 137; IGHV3- 21 subset # 2, n= 51) were sequenced on the HiSeq 2000 and data were analyzed using well- established bioinformatics tools. Using a conservative cutoff of 10% for the mutant allele, we found that 114/ 180 ( 63%) patients carried at least one mutation, with mutations in ATM, BIRC3, NOTCH1, SF3B1 and TP53 accounting for 149/ 177 ( 84%) of all mutations. We selected 155 mutations for Sanger validation ( variant allele frequency, 10- 99%) and 93% ( 144/ 155) of mutations were confirmed; notably, all 11 discordant variants had a variant allele frequency between 11- 27%, hence at the detection limit of conventional Sanger sequencing. Technical precision was assessed by repeating the entire HaloPlex procedure for 63 patients; concordance was found for 77/ 82 ( 94%) mutations. In summary, this study demonstrates that targeted next- generation sequencing is an accurate and reproducible technique potentially suitable for routine screening, eventually as a stand- alone test without the need for confirmation by Sanger sequencing.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-251831 (URN)10.3324/haematol.2014.109777 (DOI)000351279900027 ()25480502 (PubMedID)
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2015-04-27 Created: 2015-04-24 Last updated: 2017-12-04Bibliographically approved
    2. Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia
    Open this publication in new window or tab >>Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia
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    2015 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed) Published
    Abstract [en]

    NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-279237 (URN)10.1084/jem.20142009 (DOI)000355569300001 ()25987724 (PubMedID)
    Funder
    Swedish National Infrastructure for Computing (SNIC), b2011080Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), CA81554; CA081554EU, European Research Council, 259796EU, FP7, Seventh Framework Programme, 306242
    Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-01-10Bibliographically approved
    3. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations
    Open this publication in new window or tab >>Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations
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    2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 8, p. 1007-1016Article in journal (Refereed) Published
    Abstract [en]

    Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.

    National Category
    Immunology in the medical area
    Identifiers
    urn:nbn:se:uu:diva-257013 (URN)10.1182/blood-2015-10-674572 (DOI)000373397800011 ()26675346 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research CouncilEU, European Research CouncilSwedish National Infrastructure for Computing (SNIC)
    Note

    De två första författarna delar förstaförfattarskapet.

    De två sista författarna delar sistaförfattarskapet.

    Available from: 2015-06-29 Created: 2015-06-29 Last updated: 2018-01-11Bibliographically approved
    4. Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
    Open this publication in new window or tab >>Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-302024 (URN)
    External cooperation:
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2016-08-28 Created: 2016-08-28 Last updated: 2018-01-10
  • 6.
    Ljungström, Viktor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Plevova, K.
    Masaryk Univ, Dept Mol Med, CEITEC, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    Sutton, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stavroyianni, N.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Agathangelidis, A.
    Ist Sci San Raffaele, Div Mol Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rossi, D.
    Amedeo Avogadro Univ Eastern Piedmont, Div Hematol, Dept Translat Med, Novara, Italy..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Gaidano, G.
    Amedeo Avogadro Univ Eastern Piedmont, Div Hematol, Dept Translat Med, Novara, Italy..
    Davi, F.
    Hop Cochin, Hematol Lab, F-75674 Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Pott, C.
    Univ Hosp Schleswig Holstein, Med Dept 2, Kiel, Germany..
    Trentin, L.
    Univ Padua, Sch Med, Dept Med, Hematol & Clin Immunol Branch, Padua, Italy..
    Pospisilova, S.
    Masaryk Univ, Dept Mol Med, CEITEC, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    Ghia, P.
    Ist Sci San Raffaele, Div Mol Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 10-11Article in journal (Other academic)
  • 7.
    Ljungström, Viktor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Ntoufa, Stavroula
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Clifford, Ruth
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Blakemore, Stuart
    Stavroyianni, Niki
    Agathangelidis, Andreas
    Rossi, Davide
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kotaskova, Jana
    Juliusson, Gunnar
    Belessi, Chrysoula
    Chiorazzi, Nicholas
    Panagiotidis, Panagiotis
    Langerak, Anton W
    Smedby, Karin E
    Oscier, David
    Gaidano, Gianluca
    Schuh, Anna
    Davi, Frederic
    Pott, Christiane
    Strefford, Jonathan C
    Trentin, Livio
    Pospisilova, Sarka
    Ghia, Paolo
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjöblom, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 8, p. 1007-1016Article in journal (Refereed)
    Abstract [en]

    Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.

  • 8.
    Ljungström, Viktor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Agathangelidis, Andreas
    Università Vita-Salute San Raffaele, and Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
    Muggen, Alice F.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Plevova, Karla
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Rossi, Davide
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
    Davis, Zadie
    Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ntoufa, Stavroula
    Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
    Davi, Frederic
    Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
    Gaidano, Gianluca
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
    Oscier, David
    Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom.
    Pospisilova, Sarka
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Langerak, Anton W.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
    Ghia, Paolo
    Università Vita-Salute San Raffaele, and Division of Experimental Oncology and Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptorsManuscript (preprint) (Other academic)
  • 9. Malcovati, Luca
    et al.
    Karimi, Mohsen
    Papaemmanuil, Elli
    Ambaglio, Ilaria
    Jadersten, Martin
    Jansson, Monika
    Elena, Chiara
    Galli, Anna
    Walldin, Gunilla
    Della Porta, Matteo G.
    Raaschou-Jensen, Klas
    Travaglino, Erica
    Kallenbach, Klaus
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Boveri, Emanuela
    Invernizzi, Rosangela
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Campbell, Peter J.
    Cazzola, Mario
    Hellstrom-Lindberg, Eva
    Genetic Determinants of Disease Phenotype and Clinical Outcome in Myelodysplastic Syndromes with Ring Sideroblasts2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 10. Malcovati, Luca
    et al.
    Karimi, Mohsen
    Papaemmanuil, Elli
    Ambaglio, Ilaria
    Jadersten, Martin
    Jansson, Monika
    Elena, Chiara
    Galli, Anna
    Walldin, Gunilla
    Della Porta, Matteo G.
    Raaschou-Jensen, Klas
    Travaglino, Erica
    Kallenbach, Klaus
    Pietra, Daniela
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Conte, Simona
    Boveri, Emanuela
    Invernizzi, Rosangela
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Campbell, Peter J.
    Cazzola, Mario
    Lindberg, Eva Hellstrom
    SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 2, p. 233-241Article in journal (Refereed)
    Abstract [en]

    Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.

  • 11.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Noerenberg, Daniel
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mylonas, Elena
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Abdulla, Maysaa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frick, Mareike
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Asmar, Fazila
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schneider, Markus
    Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
    Yoshida, Kenichi
    Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    Skaftason, Aron
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pandzic, Tatjana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gonzalez, Blanca
    Department of Pathology, Hospital Clinic and Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
    Tasidou, Anna
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Waldhueter, Nils
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Rivas-Delgado, Alfredo
    Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Angelopoulou, Maria
    Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Ziepert, Marita
    Institute for Medical Informatics, Statistics, and Epidemiology, University at Leipzig, Leipzig, Germany.
    Arends, Christopher-Maximilian
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Couronne, Lucile
    Service d’Hematologie Adulte, Assistance Publique–Hopitaux de Paris, Hopital Necker, Paris, France.
    Lenze, Dido
    Institute of Pathology, Charite University Medical Center, Berlin, Germany.
    Claudia, Baldus
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Bastard, Christian
    INSERM U918, Universite de Rouen, Centre Henri Becquerel, Rouen, France.
    Okosun, Jessica
    Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
    Fitzgibbon, Jude
    Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
    Dörken, Bernd
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Drexler, Hans G
    Leibniz-Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
    Roos-Weil, Damien
    University Paris-Sud, Orsay, France, INSERM, U1170, Institut Gustave Roussy, Villejuif, France and Equipe Labellisee Ligue Nationale Contre le Cancer, Paris, France.
    Schmitt, Clemens A
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany.
    Munch-Petersen, Helga D
    Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Zenz, Thorsten
    Departments of Molecular Therapy in Haematology and Oncology and Translational Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, Germany, Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany and German Consortium for Translational Cancer Research, Heidelberg, Germany .
    Hansmann, Martin-Leo
    Dr. Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.
    Strefford, Jonathan C
    Academic Unit of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bernard, Olivier
    University Paris-Sud, Orsay, France, INSERM, U1170, Institut Gustave Roussy, Villejuif, France and Equipe Labellisee Ligue Nationale Contre le Cancer, Paris, France.
    Ralfkiaer, Elisabeth
    Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Erlanson, Martin
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Korkolopoulou, Penelope
    Department of Pathology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Hultdin, Magnus
    Department of Medical Biosciences, Pathology, Umeå University, Umeå Sweden.
    Papadaki, Theodora
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Grønbæk, Kirsten
    Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
    Lopez-Guillermo, Armando
    Hematology Department, Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Ogawa, Seishi
    Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
    Küppers, Ralf
    Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
    Stavroyianni, Niki
    Hematology Department and Hematopoietic Cell Transplantation Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
    Kanellis, George
    Hematopathology Department, Evangelismos Hospital, Athens, Greece.
    Rosenwald, Andreas
    Institute of Pathology, University of Würzburg, Würzburg, Germany and Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
    Campo, Elias
    Department of Pathology, Hospital Clinic and Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ott, German
    Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
    Vasslakopoulos, Theodoros P
    Department of Haematology, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece.
    Hummel, Michael
    Institute of Pathology, Charite University Medical Center, Berlin, Germany.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Damm, Frederik
    Department of Hematology, Oncology, and Tumor Immunology, Charite, University Medical Center, Berlin, Germany and Berlin Institute of Health, Berlin, Germany.
    Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. 2666-2670Article in journal (Refereed)
    Abstract [en]

    We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

  • 12.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bondza, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Arngården, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bhoi, Sujata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Falk-Sörqvist, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Plevova, Karla
    Muggen, Alice
    Yan, Xiao-Jie
    Sander, Birgitta
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Juliusson, Gunnar
    Belessi, Chrysoula
    Chiorazzi, Nicholas
    Strefford, Jonathan C.
    Langerak, Anton W.
    Pospisilova, Sarka
    Davi, Frederic
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, Paolo
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Recurrent Mutations within the Nfkbie gene: A Novel Mechanism for NF-kappa B Deregulation in Aggressive Chronic Lymphocytic Leukemia2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 13.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley-Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bondza, Sina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Arngården, Linda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Bhoi, Sujata
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Jimmy
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cortese, Diego
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Falk Sörqvist, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönn, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Muggen, Alice F.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Yan, Xiao-Jie
    The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America, .
    Sander, Birgitta
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden.
    Belessi, Chrysoula
    Hematology Department, General Hospital of Nikea, Piraeus, Greece.
    Rung, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chiorazzi, Nicholas
    The Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
    Strefford, Jonathan C.
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Langerak, Anton W.
    Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
    Pospisilova, Sarka
    Central European Institute of Technology, Masaryk University & University Hospital Brno, Brno, Czech Republic.
    Davi, Frederic
    AP-HP, Hôpital Pitié-Salpêtrière, Department of Hematology, and Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
    Hellström, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, Paolo
    Division of Experimental Oncology, Department of Onco-Haematology, IRCCS Istituto Scientifico San Raffaele, Fondazione Centro San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
    Söderberg, Ola
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. nstitute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Rosenquist Brandell, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia2015In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed)
    Abstract [en]

    NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

  • 14.
    Mathot, Lucy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Svedlund, Jessica
    Moens, Lotte
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Adlerteg, Tom
    Falk-Sörqvist, Elin
    Rendo, Verónica
    Bellomo, Claudia
    Mayrhofer, Markus
    Cortina, Carme
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Isaksson, Anders
    Moustakas, Aristidis
    Batlle, Eduard
    Birgisson, Helgi
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nilsson, Mats
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 7, no 77, p. 1730-1740Article in journal (Refereed)
    Abstract [en]

    The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.

  • 15.
    Moens, Lotte N. J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Falk-Sörqvist, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattsson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    La Fleur, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mathot, Lucy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Stockholm Univ, Sci Life Lab, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 6, p. 729-739Article in journal (Refereed)
    Abstract [en]

    In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomotecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment Length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and Lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.

  • 16.
    Navrkalova, Veronika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic..
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Radova, Lenka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ntoufa, Stavroula
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Juliusson, Gunnar
    Lund Univ, Dept Lab Med, Stem Cell Ctr, Hematol & Transplantat, Lund, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Davi, Frederic
    Hop La Pitie Salpetriere, Dept Biol Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Langerak, Anton W.
    Erasmus Univ, Dept Immunol, Med Ctr, NL-3000 DR Rotterdam, Netherlands..
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Strefford, Jonathan C.
    Univ Southampton, Canc Sci Unit, Southampton, Hants, England..
    Oscier, David G.
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Stamatopoulos, Kostas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Trbusek, Martin
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    ATM Mutations in Major Stereotyped CLL Subsets: Enrichment in Subset #2 is Associated with Unfavourable Outcome2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 17.
    Navrkalova, Veronika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic.;Masaryk Univ, CEITEC Cent European Inst Technol, Dept Mol Med, Brno, Czech Republic..
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Radova, Lenka
    Masaryk Univ, CEITEC Cent European Inst Technol, Dept Mol Med, Brno, Czech Republic..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Plevova, Karla
    Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic.;Masaryk Univ, CEITEC Cent European Inst Technol, Dept Mol Med, Brno, Czech Republic..
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ntoufa, Stavroula
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Juliusson, Gunnar
    Lund Univ, Stem Cell Ctr, Hematol & Transplantat, Dept Lab Med, Lund, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden..
    Belessi, Chrysoula
    Gen Hosp Nikea, Dept Hematol, Piraeus, Greece..
    Panagiotidis, Panagiotis
    Univ Athens, Sch Med, Dept Propaedeut Med 1, Athens, Greece..
    Touloumenidou, Tasoula
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Davi, Frederic
    Hosp Pitie Salpetriere, Hematol Lab, Paris, France.;Univ Paris 06, Paris, France..
    Langerak, Anton W.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Strefford, Jonathan C.
    Univ Southampton, Fac Med, Canc Sci, Southampton, Hants, England..
    Oscier, David
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Mayer, Jiri
    Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    Stamatopoulos, Kostas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Pospisilova, Sarka
    Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic.;Masaryk Univ, CEITEC Cent European Inst Technol, Dept Mol Med, Brno, Czech Republic..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Trbusek, Martin
    Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 9, article id e372Article in journal (Refereed)
  • 18.
    Noerenberg, Daniel
    et al.
    Univ Hosp Rudolf Virchow, Charite, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany..
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Blakemore, Stuart
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Rossi, Davide
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy..
    Clifford, Ruth
    Univ Oxford, Mol Diagnost Ctr, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford, England..
    Navrkalova, Veronika
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden..
    Juliusson, Gunnar
    Lund Univ, Stem Cell Ctr, Hematol & Transplantat, Lund, Sweden..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Panagiotidis, Panagiotis
    Univ Athens, Sch Med, Dept Propaedeut Med 1, GR-11527 Athens, Greece..
    Chiorazzi, Nicholas
    North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Davi, Frederic
    Hop La Pitie Salpetriere, Hematol Lab, Paris, France.;Univ Paris 06, Paris, France..
    Langerak, Anton W.
    Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Schuh, Anna
    Univ Oxford, Mol Diagnost Ctr, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Oxford, England..
    Gaidano, Gianluca
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy..
    Strefford, Jonathan C.
    Univ Southampton, Canc Sci Unit, Southampton, Hants, England..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Div Mol Oncol, Milan, Italy.;Univ Vita Salute San Raffaele, Dept Oncol, Milan, Italy.;Ist Sci San Raffaele, Milan, Italy..
    Stamatopoulos, Kostas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Zenz, Thorsten
    Univ Heidelberg Hosp, Dept Internal Med 5, Heidelberg, Germany.;German Consortium Translat Canc Res DKTK, Heidelberg, Germany..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Damm, Frederik
    Univ Hosp Rudolf Virchow, Charite, Dept Hematol Oncol & Tumor Immunol, Berlin, Germany..
    EGR2 Mutations in Chronic Lymphocytic Leukemia: A New Bad Player2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 19.
    Pandzic, Tatjana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    He, Liqun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ban, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. NUS, Yong Loo Lin Sch Med, A STAR, Dept Biochem,Inst Mol & Cell Biol, Singapore, Singapore..
    Ali, Muhammad Akhtar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hellström, Anders R.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Schuh, Anna
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Clifford, Ruth
    Univ Oxford, Radcliffe Dept Med, Oxford, England..
    Blakemore, Stuart J.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Strefford, Jonathan C.
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Baumann, Tycho
    Univ Southampton, Canc Sci, Fac Med, Southampton, Hants, England..
    Lopez-Guillermo, Armando
    Hosp Clin Barcelona, IDIBAPS, Serv Hematol, Barcelona, Spain..
    Campo, Elias
    Univ Barcelona, IDIBAPS, Hosp Clin, Unitat Hematol, Barcelona, Spain..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hellström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 24, p. 6217-6227Article in journal (Refereed)
    Abstract [en]

    Purpose: To identify resistance mechanisms for the chemotherapeutic drug fludarabine in chronic lymphocytic leukemia (CLL), as innate and acquired resistance to fludarabine-based chemotherapy represents a major challenge for long-term disease control. Experimental Design: We used piggyBac transposon-mediated mutagenesis, combined with next-generation sequencing, to identify genes that confer resistance to fludarabine in a human CLL cell line. Results: In total, this screen identified 782 genes with transposon integrations in fludarabine-resistant pools of cells. One of the identified genes is a known resistance mediator DCK (deoxycytidine kinase), which encodes an enzyme that is essential for the phosphorylation of the prodrug to the active metabolite. BMP2K, a gene not previously linked to CLL, was also identified as a modulator of response to fludarabine. In addition, 10 of 782 transposon-targeted genes had previously been implicated in treatment resistance based on somatic mutations seen in patients refractory to fludarabine-based therapy. Functional characterization of these genes supported a significant role for ARID5B and BRAF in fludarabine sensitivity. Finally, pathway analysis of transposon-targeted genes and RNA-seq profiling of fludarabine-resistant cells suggested deregulated MAPK signaling as involved in mediating drug resistance in CLL. Conclusions: To our knowledge, this is the first forward genetic screen for chemotherapy resistance in CLL. The screen pinpointed novel genes and pathways involved in fludarabine resistance along with previously known resistance mechanisms. Transposon screens can therefore aid interpretation of cancer genome sequencing data in the identification of genes modifying sensitivity to chemotherapy.

  • 20.
    Parker, H.
    et al.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Rose-Zerilli, M. J. J.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Larrayoz, M.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Clifford, R.
    Univ Oxford, Mol Diagnost Ctr, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England..
    Edelmann, J.
    Univ Ulm, Dept Internal Med 3, Ulm, Germany..
    Blakemore, S.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Gibson, J.
    Univ Southampton, Fac Nat & Environm Sci, Ctr Biol Sci, Southampton, Hants, England..
    Wang, J.
    Queen Marys Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wojdacz, T. K.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Chaplin, T.
    Queen Marys Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    Roghanian, A.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Parker, A.
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Tausch, E.
    Univ Ulm, Dept Internal Med 3, Ulm, Germany..
    Ntoufa, S.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Ramos, S.
    Univ Oxford, Mol Diagnost Ctr, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England..
    Robbe, P.
    Univ Oxford, Mol Diagnost Ctr, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England..
    Alsolami, R.
    Univ Oxford, Mol Diagnost Ctr, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England..
    Steele, A. J.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Packham, G.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Rodriguez-Vicente, A. E.
    Univ Salamanca, Univ Hosp Salamanca, CSIC,Dept Haematol, Comprehens Canc Ctr Res,IBMCC,Biomed Res Inst Sal, Salamanca, Spain..
    Brown, L.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    McNicholl, F.
    Altnagelvin Hosp, Western Hlth & Social Care Trust, Derry, Londonderry, North Ireland..
    Forconi, F.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Pettitt, A.
    Royal Liverpool & Broadgreen Univ Hosp NHS Trust, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England..
    Hillmen, P.
    St James Univ Hosp, Dept Haematol, Leeds, W Yorkshire, England..
    Dyer, M.
    Univ Leicester, Coll Med Biol Sci & Psychol, Leicester, Leics, England..
    Cragg, M. S.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Chelala, C.
    Oakes, C. C.
    Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stamatopoulos, K.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Stilgenbauer, S.
    Univ Ulm, Dept Internal Med 3, Ulm, Germany..
    Knight, S.
    Univ Oxford, Mol Diagnost Ctr, Biomed Res Ctr, Oxford Natl Inst Hlth Res, Oxford, England..
    Schuh, A.
    Oscier, D. G.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England.;Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Strefford, J. C.
    Univ Southampton, Fac Med, Canc Res UK Ctr, Acad Unit Canc Sci, Southampton, Hants, England.;Univ Southampton, Expt Canc Med Ctr, Southampton, Hants, England..
    Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia2016In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 11, p. 2179-2186Article in journal (Refereed)
    Abstract [en]

    Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.

  • 21.
    Parry, Marina
    et al.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Rose-Zerilli, Matthew J. J.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gibson, Jane
    Univ Southampton, Ctr Biol Sci, Southampton, Hants, England..
    Wang, Jun
    Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    Walewska, Renata
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Parker, Helen
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Parker, Anton
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Gardiner, Anne
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    McIver-Brown, Neil
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Kalpadakis, Christina
    Univ Crete, Dept Hematol, Sch Med, Iraklion, Greece..
    Xochelli, Aliki
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Div Mol Oncol, Dept Oncohaematol, IRCCS Ist Sci San Raffaele, Milan, Italy..
    de Castro, David Gonzalez
    Inst Canc Res, Heamatooncol Unit, Div Mol Pathol, Sutton, Surrey, England..
    Dearden, Claire
    Inst Canc Res, Heamatooncol Unit, Div Mol Pathol, Sutton, Surrey, England..
    Pratt, Guy
    Univ Birmingham, Sch Canc Studies, Birmingham, W Midlands, England.;Heart England NHS Fdn Trust, Dept Haematol, Birmingham, W Midlands, England..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ashton-Key, Margaret
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Forconi, Francesco
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Collins, Andrew
    Univ Southampton, Fac Med, Genet Epidemiol & Bioinformat, Southampton SO9 5NH, Hants, England..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Div Mol Oncol, Dept Oncohaematol, IRCCS Ist Sci San Raffaele, Milan, Italy..
    Matutes, Estella
    Univ Barcelona, Haematopathol Unit, Hosp Clin, Barcelona, Spain..
    Pangalis, Gerassimos
    Athens Med Ctr, Dept Hematol, Athens, Greece..
    Stamatopoulos, Kostas
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Oscier, David
    Strefford, Jonathan C.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing2015In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 18, p. 4174-4183Article in journal (Refereed)
    Abstract [en]

    Purpose:<bold> </bold>Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design:<bold> </bold>We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL. Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08-5.2; P = 0.03). Conclusions:<bold> </bold>We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

  • 22. Rose-Zerilli, Matthew J. J.
    et al.
    Parry, Marina
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gibson, Jane
    Wang, Jun
    Walewska, Renata
    Parker, Helen
    Parker, Anton
    Davis, Zadie
    Gardiner, Anne Catherine
    McIver-Brown, Neil
    Kalpadakis, Christina H.
    Xochelli, Aliki
    Anagnostopoulos, Achilles
    Fazi, Claudia
    de Castro, David Gonzalez
    Dearden, Claire
    Pratt, Guy
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ashton-Keys, Margaret
    Forconi, Francesco
    Collins, Andrew
    Ghia, Paolo
    Matutes, Estella
    Pangalis, Gerassimos A.
    Stamatopoulos, Kostas
    Oscier, David G.
    Strefford, Jonathan C.
    Deep-Sequencing Reveals the Molecular Landscape of Splenic Marginal Zone Lymphoma: Biological and Clinical Implications2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 23.
    Rose-Zerilli, Matthew John Jerome
    et al.
    Univ Southampton, Southampton, Hants, England..
    Parker, Helen
    Univ Southampton, Southampton, Hants, England..
    Larrayoz, Marta
    Univ Southampton, Canc Sci Unit, Southampton, Hants, England..
    Clifford, Ruth
    Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Mol Diagnost Ctr, Oxford, England..
    Blakemore, Stuart
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Edelmann, Jennifer
    Univ Ulm, D-89069 Ulm, Germany..
    Gibson, Jane
    Univ Southampton, Southampton, Hants, England..
    Wang, Jun
    Barts Canc Inst, London, England..
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Chaplin, Tracy
    Barts Canc Inst, London, England..
    Roghanian, Ali
    Univ Southampton, Southampton, Hants, England..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Parker, Anton
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Tausch, Eugen
    Univ Ulm, Med Ctr, Dept Internal Med 3, D-89069 Ulm, Germany..
    Ntoufa, Stavroula
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ramos, Sara
    Univ Oxford, Oxford, England..
    Robbe, Pauline
    Univ Oxford, Nuffield Dept Lab Sci, Oxford, England..
    Steele, Andrew J.
    Univ Southampton, Canc Sci Unit, Southampton, Hants, England..
    Packham, Graham
    Univ Southampton, Canc Sci Unit, Southampton, Hants, England..
    Rodriguez, Ana E.
    Univ Salamanca, Ctr Invest Canc, E-37008 Salamanca, Spain..
    Brown, Lee
    Univ Southampton, Southampton, Hants, England..
    McNicholl, Feargal
    Western Hlth & Social Care Trust, Derry, Londonderry, North Ireland..
    Forconi, Francesco
    Univ Southampton, Haematol Oncol Grp, Canc Sci Unit, Southampton, Hants, England..
    Pettitt, Andrew R.
    Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool L69 3BX, Merseyside, England..
    Hillmen, Peter
    St Jamess Inst Oncol, Leeds, W Yorkshire, England..
    Dyer, Martin J. S.
    Univ Leicester, Ernest & Helen Scott Haematol Res Inst, Leicester, Leics, England..
    Cragg, Mark S.
    Univ Southampton, Southampton Gen Hosp, Fac Med, Canc Sci Unit, Southampton, Hants, England..
    Young, Bryan D.
    QMUL, Baits & London Sch Med & Dent, Med Oncol, London, England..
    Chelala, Claude
    Barts Canc Inst, London, England..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, Kostas
    G Papanicolaou Hosp, Thessaloniki, Greece..
    Stilgenbauer, Stephan
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Knight, Samantha
    Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Mol Diagnost Ctr, Oxford, England..
    Schuh, Anna
    Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Mol Diagnost Ctr, Oxford, England..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Strefford, Jonathan C.
    Univ Southampton, Canc Sci Unit, Southampton, Hants, England..
    Genomic Disruption of the Histone Methyltransferase SETD2 in Chronic Lymphocytic Leukemia2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 24.
    Staaf, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Åkerström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hög tid att söka till nya MD/PhD-programmet vid Uppsala universitet: Tidig bro mellan preklinisk forskning och klinik2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 17-18, p. 898-898Article in journal (Refereed)
  • 25.
    Sutton, L. A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navrkalova, V.
    Malcikova, J.
    Muggen, A. F.
    Trbusek, M.
    Davi, F.
    Belessi, C.
    Langerak, A. W.
    Ghia, P.
    Pospisilova, S.
    Stamatopoulos, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, R.
    Targeted Next-Generation Sequencing for Mutational Screening in Chronic Lymphocytic Leukemia: A High-Throughput Yet Tailored Approach Will Facilitate Implementation Within a Clinical Setting2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no S1, p. 313-314Article in journal (Other academic)
  • 26.
    Sutton, Lesley Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol CEITEC, Brno, Czech Republic.
    Rossi, Davide
    Oncol Inst Southern Switzerland, Brno, Czech Republic.
    Stalika, Evangelia
    CERTH, Thermi, Greece.
    Agathangelidis, Andreas
    CERTH, Thermi, Greece.
    Scarfo, Lydia
    Osped San Raffaele, Milan, Italy.
    Muggen, Alice F.
    ErasmusMC, Rotterdam, Netherlands.
    Langerak, Anton W.
    ErasmusMC, Rotterdam, Netherlands.
    Pospisilova, Sarka
    Masaryk Univ, CEITEC, Brno, Czech Republic; Univ Hosp Brno, Dept Internal Med Hematol & Oncol, Brno, Czech Republic; Med Fac MU, Brno, Czech Republic.
    Davi, Frederic
    AP HP, Paris, France.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Milan, Italy.
    Stamatopoulos, Kostas
    IRCCS Ist Sci San Raffaele, Milan, Italy; Ctr Res & Technol Hellas, Thessaloniki, Greece.
    Brandell, Richard Rosenquist
    Karolinska Inst, Stockholm, Sweden.
    Transcriptome sequencing provides novel insights into the biology of chronic lymphocytic leukemia: focus on major stereotyped subsets2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no Supplement: 1, p. 220-221Article in journal (Other academic)
  • 27.
    Sutton, Lesley-Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Young, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navrkalova, Veronika
    Malcikova, Jitka
    Muggen, Alice F.
    Trbusek, Martin
    Panagiotidis, Panagiotis
    Davi, Frederic
    Belessi, Chrysoula
    Langerak, Anton W.
    Ghia, Paolo
    Pospisilova, Sarka
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Targeted next-generation sequencing in chronic lymphocytic leukemia: a high-throughput yet tailored approach will facilitate implementation in a clinical setting2015In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, no 3, p. 370-376Article in journal (Refereed)
    Abstract [en]

    Next- generation sequencing has revealed novel recurrent mutations in chronic lymphocytic leukemia, particularly in patients with aggressive disease. Here, we explored targeted re- sequencing as a novel strategy to assess the mutation status of genes with prognostic potential. To this end, we utilized HaloPlex targeted enrichment technology and designed a panel including nine genes: ATM, BIRC3, MYD88, NOTCH1, SF3B1 and TP53, which have been linked to the prognosis of chronic lymphocytic leukemia, and KLHL6, POT1 and XPO1, which are less characterized but were found to be recurrently mutated in various sequencing studies. A total of 188 chronic lymphocytic leukemia patients with poor prognostic features ( unmutated IGHV, n= 137; IGHV3- 21 subset # 2, n= 51) were sequenced on the HiSeq 2000 and data were analyzed using well- established bioinformatics tools. Using a conservative cutoff of 10% for the mutant allele, we found that 114/ 180 ( 63%) patients carried at least one mutation, with mutations in ATM, BIRC3, NOTCH1, SF3B1 and TP53 accounting for 149/ 177 ( 84%) of all mutations. We selected 155 mutations for Sanger validation ( variant allele frequency, 10- 99%) and 93% ( 144/ 155) of mutations were confirmed; notably, all 11 discordant variants had a variant allele frequency between 11- 27%, hence at the detection limit of conventional Sanger sequencing. Technical precision was assessed by repeating the entire HaloPlex procedure for 63 patients; concordance was found for 77/ 82 ( 94%) mutations. In summary, this study demonstrates that targeted next- generation sequencing is an accurate and reproducible technique potentially suitable for routine screening, eventually as a stand- alone test without the need for confirmation by Sanger sequencing.

  • 28.
    Young, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Noerenberg, Daniel
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Frick, Mareike
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Blakemore, Stuart James
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Galan-Sousa, Joel
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Plevova, Karla
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rossi, Davide
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy and Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.
    Ruth, Clifford
    Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
    Roos-Weil, Damien
    INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
    Navrklova, Veronika
    European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Dörken, Bernd
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Schmitt, Clemens A
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Ekström Smedby, Karin
    Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Lund University, Lund, Sweden.
    Giacopelli, Brian
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Blachly, James
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Belessi, Chrysoula
    Hematology Department, General Hospital of Nikea, Piraeus, Greece.
    Panayiotidis, Panayiotis
    First Department of Propaedeutic Medicine, School of Medicine, University of Athens, Athens, Greece.
    Chiorazzi, Nicholas
    Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Davi, Frédéric
    Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
    Langerak, Anton W
    Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
    Oscier, David
    Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
    Schuh, Anna
    Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
    Gaidano, Gianluca
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
    Ghia, Paolo
    Università Vita-Salute San Raffaele, Milan, Italy and Division of Experimental Oncology and Department of Onco-Hematology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
    Xu, Wei
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Fan, Lei
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Bernard, Olivier A
    INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
    Nguyen-Khac, Florence
    Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
    Rassenti, Laura Z
    Division of Hematology/Oncology, Department of Medicine, University of California at San Diego/Moores Cancer Center, La Jolla, CA, USA.
    Li, Jianyonglm
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Kipps, Thomas J
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden and Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
    Pospisilova, Sarka
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Zenz, Thorsten
    Department of Molecular Therapy in Haematology and Oncology (G250) and Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
    Strefford, Jonathan
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Damm, Frederik
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany; German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany and Berlin Institute of Health (BIH), Berlin, Germany .
    EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1547-1554Article in journal (Refereed)
    Abstract [en]

    Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

  • 29.
    Young, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norenberg, Daniel
    Charite, Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany..
    Ljungstrom, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Baliakas, Panagiotis
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rossi, Davide
    Amedeo Avogadro Univ Eastern Piedmont, Novara, Italy..
    Navrkalova, Veronika
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smedby, Karin Ekstrom
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden..
    Juliusson, Gunnar
    Lund Univ, Dept Lab Med, Stem Cell Ctr Hematol & Transplantat, Lund, Sweden..
    Belessi, Chrysoula
    Gen Hosp Nikea, Dept Hematol, Piraeus, Greece..
    Panagiotidis, Panagiotis
    Univ Athens, Sch Med, Dept Propaedeut Med 1, GR-11527 Athens, Greece..
    Chiorazzi, Nicholas
    Feinstein Inst Med Res, North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA..
    Davi, Frederic
    Hop La Pitie Salpetriere, Hematol Lab, Paris, France.;Univ Paris 06, 12 Rue Cuvier, Paris, France..
    Langerak, Anton W.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Gaidano, Gianluca
    Ghia, Paolo
    IRCCS, San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS, San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Stamatopoulos, Kostas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Zenz, Thorsten
    Univ Heidelberg Hosp, Dept Med 5, Heidelberg, Germany..
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Damm, Frederik
    Charite, Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany..
    EGR2 mutations in chronic lymphocytic leukemiam - a new bad player?2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no S1, p. 83-85Article in journal (Other academic)
1 - 29 of 29
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