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Ljungström, Viktor
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Publications (10 of 31) Show all publications
Agathangelidis, A., Ljungström, V., Scarfo, L., Fazi, C., Gounari, M., Pandzic, T., . . . Ghia, P. (2018). Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations. Haematologica, 103(5), 865-873
Open this publication in new window or tab >>Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations
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2018 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 5, p. 865-873Article in journal (Refereed) Published
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.

National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-356089 (URN)10.3324/haematol.2017.177212 (DOI)000431396200029 ()29449433 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer SocietyEU, European Research Council
Available from: 2018-07-19 Created: 2018-07-19 Last updated: 2018-07-19Bibliographically approved
Ljungström, V. & Rosenquist, R. (2018). Not so lost in translation: RPS15 mutations in CLL. Blood, 132(22), 2317-2319
Open this publication in new window or tab >>Not so lost in translation: RPS15 mutations in CLL
2018 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132, no 22, p. 2317-2319Article in journal, Editorial material (Other academic) Published
Abstract [en]

In this issue of Blood, Bretones et al expand knowledge of the functional consequences of recurrent mutations in RPS15, a gene that encodes a ribosomal protein of the 40S subunit and is enriched in patients with clinically aggressive chronic lymphocytic leukemia (CLL).(1) By transfecting RPS15 mutants and applying different technologies to assess ribosome activity and efficiency in combination with high-throughput proteome profiling, they were able to demonstrate reduced half-life of RPS15, impaired translational fidelity, and changes in the expressed proteome in mutant vs wild-type RPS15.

Place, publisher, year, edition, pages
AMER SOC HEMATOLOGY, 2018
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-372515 (URN)10.1182/blood-2018-09-875179 (DOI)000451634400003 ()30498067 (PubMedID)
Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Young, E., Noerenberg, D., Mansouri, L., Ljungström, V., Frick, M., Sutton, L. A., . . . Damm, F. (2017). EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia, 31(7), 1547-1554
Open this publication in new window or tab >>EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
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2017 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 7, p. 1547-1554Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-314928 (URN)10.1038/leu.2016.359 (DOI)000404745300009 ()27890934 (PubMedID)
Note

E.Y. and D.N. contributed equally to this study as joint first authors.

R.R. and F.D. contributed equally as joint senior authors.

Available from: 2017-02-07 Created: 2017-02-07 Last updated: 2017-09-28Bibliographically approved
Mathot, L., Kundu, S., Ljungström, V., Svedlund, J., Moens, L., Adlerteg, T., . . . Sjöblom, T. (2017). Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer. Cancer Research, 7(77), 1730-1740
Open this publication in new window or tab >>Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 7, no 77, p. 1730-1740Article in journal (Refereed) Published
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.

National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319146 (URN)10.1158/0008-5472.CAN-16-1921 (DOI)000398262400019 ()28108514 (PubMedID)
Funder
Swedish Cancer Society, 2006/2154; 2007/775; 2012/834EU, European Research Council, 601939Swedish Foundation for Strategic Research , F06-0050Vinnova
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2019-03-29
Sutton, L. A., Cortese, D., Ljungström, V., Plevova, K., Rossi, D., Stalika, E., . . . Brandell, R. R. (2017). Transcriptome sequencing provides novel insights into the biology of chronic lymphocytic leukemia: focus on major stereotyped subsets. Paper presented at XVII International Workshop on Chronic Lymphocytic Leukemia 2017 May 12-15, 2017, New York.. Leukemia and Lymphoma, 58(Supplement: 1), 220-221
Open this publication in new window or tab >>Transcriptome sequencing provides novel insights into the biology of chronic lymphocytic leukemia: focus on major stereotyped subsets
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2017 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no Supplement: 1, p. 220-221Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-350213 (URN)10.1080/10428194.2017.1377942 (DOI)000423431100196 ()
Conference
XVII International Workshop on Chronic Lymphocytic Leukemia 2017 May 12-15, 2017, New York.
Funder
Swedish Cancer Society
Note

Meeting Abstract: 227

Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2018-05-08Bibliographically approved
Navrkalova, V., Young, E., Baliakas, P., Radova, L., Sutton, L.-A., Plevova, K., . . . Trbusek, M. (2016). ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres [Letter to the editor]. Haematologica, 101(9), Article ID e372.
Open this publication in new window or tab >>ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 9, article id e372Article in journal, Letter (Refereed) Published
Keywords
chronic lymphocytic leukemia, stereotyped subset, ATM mutation, short telomere, antigenic selection
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-316640 (URN)10.3324/haematol.2016.142968 (DOI)000392547200020 ()27479817 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilEU, European Research Council
Available from: 2017-03-06 Created: 2017-03-06 Last updated: 2017-11-29Bibliographically approved
Ljungström, V. (2016). Exploring next-generation sequencing in chronic lymphocytic leukemia. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Exploring next-generation sequencing in chronic lymphocytic leukemia
2016 (English)Doctoral 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. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1251
Keywords
CLL, next-generation sequencing, clonal evolution, stereotypy, RPS15, NFKBIE
National Category
Medical Genetics Medical and Health Sciences
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-302026 (URN)978-91-554-9674-6 (ISBN)
Public defence
2016-10-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds v 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-09-22 Created: 2016-08-29 Last updated: 2018-01-10
Mansouri, L., Noerenberg, D., Young, E., Mylonas, E., Abdulla, M., Frick, M., . . . Damm, F. (2016). Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood, 128(23), 2666-2670
Open this publication in new window or tab >>Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
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2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. 2666-2670Article in journal (Refereed) Published
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.

National Category
Hematology Clinical Laboratory Medicine
Research subject
Molecular Genetics; Pathology
Identifiers
urn:nbn:se:uu:diva-314939 (URN)10.1182/blood-201603-704528 (DOI)000392652300015 ()27670424 (PubMedID)
Funder
German Research Foundation (DFG), DA1787/1-1Swedish Cancer SocietySwedish Research Council
Note

L.M., D.N., and E.Y. contributed equally to this study as joint first authors.

R.R. and F.D. contributed equally as joint senior authors.

Available from: 2017-02-07 Created: 2017-02-07 Last updated: 2019-03-29Bibliographically approved
Parker, H., Rose-Zerilli, M. J., Larrayoz, M., Clifford, R., Edelmann, J., Blakemore, S., . . . Strefford, J. C. (2016). Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia, 30(11), 2179-2186
Open this publication in new window or tab >>Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia
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2016 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 30, no 11, p. 2179-2186Article in journal (Refereed) Published
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.

National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-310770 (URN)10.1038/leu.2016.134 (DOI)000387803100008 ()27282254 (PubMedID)
Funder
German Research Foundation (DFG), SFB 1074 B1 B2Swedish Cancer SocietySwedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

De tre första författarna delar förstaförfattarskapet.

Available from: 2016-12-19 Created: 2016-12-19 Last updated: 2017-11-29Bibliographically approved
Karimi, M., Ljungström, V., Hansen, J. W., Kittang, A. O., Holm, M. S., Dybedal, I., . . . Hellström-Lindberg, E. (2016). Molecular Profiling In A Population Based Cohort Of Nordic Myelodysplastic Syndrome Patients. Paper presented at 21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK. Haematologica, 101, 72-72
Open this publication in new window or tab >>Molecular Profiling In A Population Based Cohort Of Nordic Myelodysplastic Syndrome Patients
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 72-72Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-301445 (URN)000379484600154 ()
Conference
21st Congress of the European-Hematology-Association, JUN 09-12, 2016, Copenhagen, DENMARK
Available from: 2016-08-24 Created: 2016-08-23 Last updated: 2017-11-28Bibliographically approved
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