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Berglund, Mattias
Publications (10 of 32) Show all publications
Abdulla, M., Laszlo, S., Triumf, J., Hedström, G., Berglund, M., Enblad, G. & Amini, R.-M. (2017). Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research [Letter to the editor]. Acta Oncologica, 56(1), 106-109
Open this publication in new window or tab >>Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research
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2017 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, p. 106-109Article in journal, Letter (Refereed) Published
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-317101 (URN)10.1080/0284186X.2016.1245863 (DOI)000392819600018 ()27796168 (PubMedID)
Available from: 2017-03-10 Created: 2017-03-10 Last updated: 2019-03-29Bibliographically approved
Delforoush, M., Berglund, M., Edqvist, P.-H., Sundström, C., Gullbo, J. & Enblad, G. (2017). Expression of possible targets for new proteasome inhibitors in diffuse large B-cell lymphoma. European Journal of Haematology, 98(1), 52-56
Open this publication in new window or tab >>Expression of possible targets for new proteasome inhibitors in diffuse large B-cell lymphoma
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2017 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 1, p. 52-56Article in journal (Refereed) Published
Abstract [en]

Objectives: Investigating expression of possible targets for proteasome inhibitors in patients with diffuse large B-cell lymphoma (DLBCL) and correlating the findings to clinical parameters and outcome.

Methods: Tumour material from 92 patients with DLBCL treated with either R-CHOP like (n = 69) or CHOP like (n = 23) regimens were stained for possible targets of proteasome inhibitors.

Results: The primary target molecule of bortezomib, proteasome subunit beta, type 5 (PSMB5), was not detected in the tumour cells in any of the cases but showed an abundant expression in cells in the microenvironment. However, the deubiquitinases (DUBs) of the proteasome, the ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) and the ubiquitin specific peptidase 14 (USP14), were detected in the cytoplasm of the tumour cells in 77% and 74% of the cases, respectively. The adhesion regulating molecule 1 (ADRM1) was detected in 98% of the cases. There was no correlation between the expression of any of the studied markers and clinical outcome or GC/non-GC phenotype.

Conclusions: We suggest that UCHL5 and/or USP14 should be further evaluated as new targets for proteasome inhibitors in DLBCL. The lack of expression of PSMB5 on the tumour cells might provide an explanation of the relatively poor results of bortezomib in DLBCL.

Keywords
proteasome inhibitors, UCHL5, USP14
National Category
Medical and Health Sciences Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-280542 (URN)10.1111/ejh.12784 (DOI)000393166600008 ()27301795 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-03-11 Created: 2016-03-11 Last updated: 2017-11-30Bibliographically approved
Pommerenke, C., Hauer, V., Zaborski, M., MacLeod, R. A., Nagel, S., Amini, R.-M., . . . Quentmeier, H. (2016). Chromosome 11q23 aberrations activating FOXR1 in B-cell lymphoma [Letter to the editor]. Blood Cancer Journal, 6, Article ID e433.
Open this publication in new window or tab >>Chromosome 11q23 aberrations activating FOXR1 in B-cell lymphoma
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2016 (English)In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 6, article id e433Article in journal, Letter (Refereed) Published
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-299971 (URN)10.1038/bcj.2016.43 (DOI)000377506100005 ()27284737 (PubMedID)
Available from: 2016-08-01 Created: 2016-08-01 Last updated: 2019-03-29Bibliographically approved
Quentmeier, H., Pommerenke, C., Nagel, S., Hauer, V., Zaborski, M., Amini, R. M., . . . Drexler, H. G. (2015). FOXR1 Activation in B-Cell Lymphoma. Paper presented at 57th Annual Meeting of the American-Society-of-Hematology, DEC 05-08, 2015, Orlando, FL. Blood, 126(23)
Open this publication in new window or tab >>FOXR1 Activation in B-Cell Lymphoma
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-283006 (URN)000368020101260 ()
Conference
57th Annual Meeting of the American-Society-of-Hematology, DEC 05-08, 2015, Orlando, FL
Available from: 2016-04-13 Created: 2016-04-08 Last updated: 2017-11-30Bibliographically approved
Hedström, G., Peterson, S., Berglund, M., Jerkeman, M. & Enblad, G. (2015). Male gender is an adverse risk factor only in young patients with diffuse large B-cell lymphoma - a Swedish population-based study. Acta Oncologica, 54(6), 924-932
Open this publication in new window or tab >>Male gender is an adverse risk factor only in young patients with diffuse large B-cell lymphoma - a Swedish population-based study
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2015 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 6, p. 924-932Article in journal (Refereed) Published
Abstract [en]

Background. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas. Five clinical adverse risk factors are merged into the International Prognostic Index (IPI), which is the major tool for prognostication. In contrast to Hodgkin's lymphoma, gender is not considered as an adverse risk factor for DLBCL patients. As we clinically had observed a very good survival rate in young female patients we hypothesised that there was a gender difference in survival due to the hormonal status of the patient. Material and methods. We conducted a registry-based retrospective cohort study of all Swedish DLBCL patients diagnosed between 2000 and 2013, to evaluate the impact of gender for survival from DLBCL. Results. In total, 7166 patients were included for further analysis. No survival difference was found between the genders when the entire population was analysed. However, analysis of 880 young patients of pre-menopausal age (i.e. 52 years) revealed that women had a longer survival compared to men of the same age group (p = 0.007). This was not found for patients older than menopausal age. In a relative survival multifactorial model adjusted for stage, ECOG performance status, serum lactate dehydrogenase and two or more extranodal sites, male gender was found to be an adverse risk factor for patients younger than 52 years (RR 1.51, 95% CI 1.14-1.88), but not for older patients (RR 0.99, 95% CI 0.89-1.10). Conclusion. This is one of the largest population-based studies of DLBCL presented to date. Most interestingly, we found male gender to be a significant adverse risk factor compared to fertile women whereas we found no survival differences between genders in the older sub-population.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-256117 (URN)10.3109/0284186X.2015.1026455 (DOI)000354479800016 ()25843161 (PubMedID)
Available from: 2015-06-23 Created: 2015-06-22 Last updated: 2017-12-04Bibliographically approved
Strömberg, T., Feng, X., Delforoush, M., Berglund, M., Lin, Y., Axelson, M., . . . Enblad, G. (2015). Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells. Medical Oncology, 32(7), Article ID 188.
Open this publication in new window or tab >>Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells
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2015 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 7, article id 188Article in journal (Refereed) Published
Abstract [en]

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP-AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by inhibition of proliferation. Pretreatment of U-2932 or U-2940 cell lines with PPP at biologically active concentrations did not prevent ligand-induced phosphorylation of IGF-1R at Tyr1131/1136 or its downstream targets AKT and ERK1/2. In contrast, the IGF-1R inhibitor NVP-AEW541 clearly inhibited phosphorylation of IGF-1R and AKT, while ERK1/2 phosphorylation was less affected. Taken together, the inhibitory effects of PPP in DLBCL cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease. However, we suggest that the primary target of PPP in these cells is not related to inhibition of IGF-1R phosphorylation.

Keywords
Diffuse large B-cell lymphoma, DLBCL, Picropodophyllin, PPP, IGF-1R
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-256985 (URN)10.1007/s12032-015-0630-y (DOI)000355619300007 ()
Available from: 2015-07-01 Created: 2015-06-29 Last updated: 2017-12-04Bibliographically approved
Kwiecinska, A., Ichimura, K., Berglund, M., Dinets, A., Sulaiman, L., Collins, V. P., . . . Lagercrantz, S. B. (2014). Amplification of 2p as a Genomic Marker for Transformation in Lymphoma. Genes, Chromosomes and Cancer, 53(9), 750-768
Open this publication in new window or tab >>Amplification of 2p as a Genomic Marker for Transformation in Lymphoma
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2014 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 53, no 9, p. 750-768Article in journal (Refereed) Published
Abstract [en]

To outline further genetic mechanisms of transformation from follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL), we have performed whole genome array-CGH in 81 tumors from 60 patients [29 de novo DLBCL (dnDLBCL), 31 transformed DLBCL (tDLBCL), and 21 antecedent FL]. In 15 patients, paired tumor samples (primary FL and a subsequent tDLBCL) were available, among which three possessed more than two subsequent tumors, allowing us to follow specific genetic alterations acquired before, during, and after the transformation. Gain of 2p15-16.1 encompassing, among others, the REL, BCL11A, USP34, COMMD1, and OTX1 genes was found to be more common in the tDLBCL compared with dnDLBCL (P < 0.001). Furthermore, a high-level amplification of 2p15-16.1 was also detected in the FL stage prior to transformation, indicating its importance during the transformation event. Quantitative real-time PCR showed a higher level of amplification of REL, USP34, and COMMD1 (all involved in the NF kappa B-pathway) compared with BCL11A, which indicates that the altered genes disrupting the NF kappa B pathway may be the driver genes of transformation rather than the previously suggested BCL11A. Moreover, a 17q21.33 amplification was exclusively found in tDLBCL, never in FL (P < 0.04) or dnDLBCL, indicating an upregulation of genes of importance during the later phase of transformation. Taken together, our study demonstrates potential genomic markers for disease progression to clinically more aggressive forms. We also confirm the importance of the TP53-, CDKN2A-, and NF kappa B-pathways for the transformation from FL to DLBCL.

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-230933 (URN)10.1002/gcc.22184 (DOI)000339670200004 ()
Available from: 2014-09-04 Created: 2014-09-01 Last updated: 2018-01-11Bibliographically approved
Hedström, G., Thunberg, U., Amini, R.-M., Zainuddin, N., Enblad, G. & Berglund, M. (2014). The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma. European Journal of Haematology, 93(6), 500-508
Open this publication in new window or tab >>The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma
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2014 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 6, p. 500-508Article in journal (Refereed) Published
Abstract [en]

Introduction: The murine double minute 2 (MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 (SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers. Patients and methods: In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis. Results: Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival (P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients (P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aaIPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis. Conclusion: Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma (DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-219350 (URN)10.1111/ejh.12388 (DOI)000345302700006 ()24889555 (PubMedID)
Available from: 2014-02-27 Created: 2014-02-27 Last updated: 2017-12-05Bibliographically approved
Foo, J. N., Smedby, K. E., Akers, N. K., Berglund, M., Irwan, I. D., Jia, X., . . . Liu, J. (2013). Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk. American Journal of Human Genetics, 93(1), 167-172
Open this publication in new window or tab >>Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk
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2013 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 1, p. 167-172Article in journal (Refereed) Published
Abstract [en]

Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 x 10(-15)). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 x 10(-14)). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-206444 (URN)10.1016/j.ajhg.2013.05.020 (DOI)000321804500017 ()
Note

De två (2) första författarna delar förstaförfattarskapet.

De två (2) sista författarna delar sistaförfattarskapet.

Available from: 2013-09-02 Created: 2013-08-30 Last updated: 2017-12-06Bibliographically approved
de Miranda, N. F. C., Peng, R., Georgiou, K., Wu, C., Sörqvist, E. F., Berglund, M., . . . Pan-Hammarstrom, Q. (2013). DNA repair genes are selectively mutated in diffuse large B cell lymphomas. Journal of Experimental Medicine, 210(9), 1729-1742
Open this publication in new window or tab >>DNA repair genes are selectively mutated in diffuse large B cell lymphomas
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2013 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 210, no 9, p. 1729-1742Article in journal (Refereed) Published
Abstract [en]

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-208076 (URN)10.1084/jem.20122842 (DOI)000323644800009 ()
Note

De två (2) första författarna delar förstaförfattarskapet.

Available from: 2013-09-24 Created: 2013-09-23 Last updated: 2017-12-06Bibliographically approved
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