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Djureinovic, Tatjana
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Publications (10 of 13) Show all publications
Abdulla, M., Hollander, P., Pandzic, T., Mansouri, L., Ednersson, S. B., Andersson, P.-O., . . . Amini, R.-M. (2019). Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma. American Journal of Hematology
Open this publication in new window or tab >>Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma
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2019 (English)In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652Article in journal (Refereed) Epub ahead of print
Abstract [en]

The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

National Category
Hematology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-397669 (URN)10.1002/ajh.25666 (DOI)000495085000001 ()31659781 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2020-01-31Bibliographically approved
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
Larsson, C., Ali, M. A., Djureinovic, T., Lindroth, A. M., He, L. & Sjöblom, T. (2017). Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition. BMC Cancer, 17, Article ID 487.
Open this publication in new window or tab >>Loss of DIP2C in RKO cells stimulates changes in DNA methylation and epithelial-mesenchymal transition
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2017 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 487Article in journal (Refereed) Published
Abstract [en]

Background: The disco-interacting protein 2 homolog C (DIP2C) gene is an uncharacterized gene found mutated in a subset of breast and lung cancers. To understand the role of DIP2C in tumour development we studied the gene in human cancer cells.

Methods: We engineered human DIP2C knockout cells by genome editing in cancer cells. The growth properties of the engineered cells were characterised and transcriptome and methylation analyses were carried out to identify pathways deregulated by inactivation of DIP2C. Effects on cell death pathways and epithelial-mesenchymal transition traits were studied based on the results from expression profiling.

Results: Knockout of DIP2C in RKO cells resulted in cell enlargement and growth retardation. Expression profiling revealed 780 genes for which the expression level was affected by the loss of DIP2C, including the tumour-suppressor encoding CDKN2A gene, the epithelial-mesenchymal transition (EMT) regulator-encoding ZEB1, and CD44 and CD24 that encode breast cancer stem cell markers. Analysis of DNA methylation showed more than 30,000 sites affected by differential methylation, the majority of which were hypomethylated following loss of DIP2C. Changes in DNA methylation at promoter regions were strongly correlated to changes in gene expression, and genes involved with EMT and cell death were enriched among the differentially regulated genes. The DIP2C knockout cells had higher wound closing capacity and showed an increase in the proportion of cells positive for cellular senescence markers.

Conclusions: Loss of DIP2C triggers substantial DNA methylation and gene expression changes, cellular senescence and epithelial-mesenchymal transition in cancer cells.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keywords
Cancer, DIP2C, Gene knockout, rAAV-mediated gene targeting, Tumour cell biology, DNA methylation, Epithelial-mesenchymal transition (EMT)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-331232 (URN)10.1186/s12885-017-3472-5 (DOI)000405865300001 ()28716088 (PubMedID)
Funder
Swedish Cancer Society, 2006/2154, 2007/775, 2012/834, 2012/1235Swedish Foundation for Strategic Research , F06-0050, RBa08-0114Swedish Society for Medical Research (SSMF)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-29Bibliographically approved
Karlsson, H., Fryknäs, M., Strese, S., Gullbo, J., Westman, G., Bremberg, U., . . . Nygren, P. (2017). Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity. OncoTarget, 8(18), 30217-30234
Open this publication in new window or tab >>Mechanistic characterization of a copper containing thiosemicarbazone with potent antitumor activity
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 18, p. 30217-30234Article in journal (Refereed) Published
Abstract [en]

Background: The thiosemicarbazone CD 02750 (VLX50) was recently reported as a hit compound in a phenotype-based drug screen in primary cultures of patient tumor cells. We synthesized a copper complex of VLX50, denoted VLX60, and characterized its antitumor and mechanistic properties.

Materials and Methods: The cytotoxic effects and mechanistic properties of VLX60 were investigated in monolayer cultures of multiple human cell lines, in tumor cells from patients, in a 3-D spheroid cell culture system and in vivo and were compared with those of VLX50.

Results: VLX60 showed >= 3-fold higher cytotoxic activity than VLX50 in 2-D cultures and, in contrast to VLX50, retained its activity in the presence of additional iron. VLX60 was effective against non-proliferative spheroids and against tumor xenografts in vivo in a murine model. In contrast to VLX50, gene expression analysis demonstrated that genes associated with oxidative stress were considerably enriched in cells exposed to VLX60 as was induction of reactive oxygen. VLX60 compromised the ubiquitin-proteasome system and was more active in BRAF mutated versus BRAF wild-type colon cancer cells.

Conclusions: The cytotoxic effects of the copper thiosemicarbazone VLX60 differ from those of VLX50 and shows interesting features as a potential antitumor drug, notably against BRAF mutated colorectal cancer.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
cancer drug, thiosemicarbazone, spheroid, VLX60, BRAF
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-323035 (URN)10.18632/oncotarget.16324 (DOI)000400456200055 ()28415818 (PubMedID)
Funder
Swedish Cancer SocietySwedish Foundation for Strategic Research
Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2017-11-29Bibliographically approved
Pandzic, T., Rendo, V., Lim, J., Larsson, C., Larsson, J., Stoimenov, I., . . . Sjöblom, T. (2017). Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth. OncoTarget, 8(58), 98646-98659
Open this publication in new window or tab >>Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 98646-98659Article in journal (Refereed) Published
Abstract [en]

The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C-terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345974 (URN)10.18632/oncotarget.21713 (DOI)000419392300074 ()
Funder
Swedish Foundation for Strategic Research , F06-0050 RBa08-0114Swedish Cancer Society, 2006/2154 2007/775 2012/834
Available from: 2018-03-13 Created: 2018-03-13 Last updated: 2018-09-20Bibliographically approved
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: 2020-01-03Bibliographically approved
Pandzic, T., Larsson, J., He, L., Kundu, S., Ban, K., Ali, M. A., . . . Hellström, M. (2016). Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia. Clinical Cancer Research, 22(24), 6217-6227
Open this publication in new window or tab >>Transposon Mutagenesis Reveals Fludarabine Resistance Mechanisms in Chronic Lymphocytic Leukemia
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 24, p. 6217-6227Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-315914 (URN)10.1158/1078-0432.CCR-15-2903 (DOI)000391472400028 ()26957556 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish National Infrastructure for Computing (SNIC), b2014071
Available from: 2017-02-23 Created: 2017-02-23 Last updated: 2017-11-29Bibliographically approved
Ljungström, V., Cortese, D., Young, E., Pandzic, T., Mansouri, L., Plevova, K., . . . Rosenquist, R. (2016). Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations. Blood, 127(8), 1007-1016
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
Stoimenov, I., Ali, M. A., Pandzic, T. & Sjöblom, T. (2015). Computational and molecular tools for scalable rAAV-mediated genome editing. Nucleic Acids Research, 43(5), Article ID e30.
Open this publication in new window or tab >>Computational and molecular tools for scalable rAAV-mediated genome editing
2015 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 5, article id e30Article in journal (Refereed) Published
Abstract [en]

The rapid discovery of potential driver mutations through large-scale mutational analyses of human cancers generates a need to characterize their cellular phenotypes. Among the techniques for genome editing, recombinant adeno-associated virus (rAAV)-mediated gene targeting is suited for knock-in of single nucleotide substitutions and to a lesser degree for gene knock-outs. However, the generation of gene targeting constructs and the targeting process is time-consuming and labor-intense. To facilitate rAAV-mediated gene targeting, we developed the first software and complementary automation-friendly vector tools to generate optimized targeting constructs for editing human protein encoding genes. By computational approaches, rAAV constructs for editing similar to 71% of bases in protein-coding exons were designed. Similarly, similar to 81% of genes were predicted to be targetable by rAAV-mediated knock-out. A Gateway-based cloning system for facile generation of rAAV constructs suitable for robotic automation was developed and used in successful generation of targeting constructs. Together, these tools enable automated rAAV targeting construct design, generation as well as enrichment and expansion of targeted cells with desired integrations.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-252714 (URN)10.1093/nar/gku1286 (DOI)000352487100003 ()25488813 (PubMedID)
Available from: 2015-05-11 Created: 2015-05-11 Last updated: 2017-12-04Bibliographically approved
Ljungström, V., Cortese, D., Young, E., Pandzic, T., Mansouri, L., Plevova, K., . . . Rosenquist, R. (2015). DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION. Paper presented at 20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA. Haematologica, 100, 10-11
Open this publication in new window or tab >>DISSECTING RESISTANCE MECHANISMS IN CHRONIC LYMPHOCYTIC LEUKEMIA USING WHOLE-EXOME SEQUENCING: IMPACT OF RECURRENT RPS15 MUTATIONS ON P53 DYSREGULATION
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2015 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 10-11Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-266165 (URN)000361204901021 ()
Conference
20th Congress of European-Hematology-Association, JUN 11-14, 2015, Vienna, AUSTRIA
Available from: 2015-11-11 Created: 2015-11-05 Last updated: 2017-12-01Bibliographically approved
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