scholarly journals The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma

2020 ◽  
Vol 143 (6) ◽  
pp. 520-528
Author(s):  
Yang Xia ◽  
Xinlian Zhang
Keyword(s):  
B Cell ◽  
Clinical Outcomes ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Novel Therapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

MYC, as a powerful transcription factor, plays a vital role in various cancers. The clinical significance of MYC alterations in diffuse large B-cell lymphoma (DLBCL) has been investigated for a long time. In this study, we comprehensively summarize the different alterations of MYC in DLBCL, including MYC overexpression, <i>MYC</i> translocations, <i>MYC</i> mutations, and increased gene copy number of <i>MYC</i>. Noteworthy, lone MYC overexpression or <i>MYC</i> translocation is not significantly associated with poor clinical outcomes, and their detrimental effects depend on the genetic alterations of BCL2 or BCL6. Both double-expressor DLBCL (DE-DLBCL), defined as overexpression of MYC and BCL2 proteins, and double-hit lymphoma (DHL), defined as a dual translocation of <i>MYC</i> together with <i>BCL2</i> or <i>BCL6</i>, represent the distinct subgroups of DLBCL with inferior clinical outcomes. The mechanism may be that MYC activation induces cell proliferation, without the threat of the apoptotic brake in the presence of BCL2 overexpression. In addition, most of <i>MYC</i> mutations are present with favorable prognosis, and the nonsignificant effect of MYC copy number amplification has been observed. It has been proved that cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab show limited effects for DHL or DE-DLBCL, and the rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin seem to be efficacious for DHL. The novel therapy is urgently needed for clinical improvement in DHL and DE-DLBCL.

MEF2B Mutations Lead to De-Regulated Expression of the BCL6 Oncogene in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1284-1284
Author(s):  
Carol Y Ying ◽  
David Dominguez-Sola ◽  
Melissa Fabi ◽  
Ivo C Lorenz ◽  
Mukesh Bansal ◽  
...  
Keyword(s):  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Transcriptional Activity ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 1284 Diffuse large B-cell lymphoma (DLBCL) and Follicular Lymphoma (FL) are the most common forms of non-Hodgkin's lymphoma in the adult, accounting for approximately 75% of lymphoma diagnoses. Recent technological advances, including whole-genome DNA and RNA sequencing and gene copy-number analysis, have provided a comprehensive view of the genomic landscape of DLBCL, allowing new insights in the somatic genetic lesions that are associated with the pathogenesis of this malignancy. Among the genetic alterations that are recurrently found in DLBCL and FL, but remain of unclear functional significance, are the mutations involving the MEF2B gene. MEF2B is a member of the myocyte enhancer-binding factor 2 (MEF2) family of transcription factors whose activity is dependent on association with specific co-repressors (including CABIN1 and HDACs) and co-activators in response to multiple signaling pathways. Overall, ∼11% of DLBCL and ∼12% of FL cases reported carry mutations in MEF2B (Morin Nature 2011; Pasqualucci Nat Genet 2011; Lohr PNAS 2012). We showed that within the mature B-cell lineage, MEF2B expression is restricted to germinal center (GC) B-cells. The analysis of the B-cell interactome, a network of protein-protein and protein-DNA interactions generated by reverse-engineering a large dataset of B-cell phenotypes, showed that MEF2B was uniquely connected to BCL6, a proto-oncogene and well-characterized master regulator of the GC reaction. We demonstrated that MEF2B directly binds to the promoter of BCL6 and leads to its trans-activation in GC B-cells. Consistently, silencing of MEF2B in GC-derived lymphoma cell lines led to BCL6 down-regulation and impairment of cell cycle progression and proliferation, suggesting that normal and malignant GC cells are dependent on MEF2B expression. Approximately 80% of the DLBCL and FL mutated cases carry missense mutations clustered in the N-terminal conserved MADS-box and MEF2 functional domains, suggesting that they may have a relevant impact on MEF2B function. In a second group of cases (∼20%), mutations affect the C-terminal half of the MEF2B protein, and are mostly represented by frameshift and nonsense mutations, which truncate or modify the C-terminus of the protein. In order to functionally characterize these mutations, we first investigated whether DLBCL- and FL-associated MEF2B mutations affected the ability to regulate the transcription of BCL6. Using a reporter construct containing the native BCL6 promoter region responsive to MEF2B, we demonstrated that most of the N-terminal mutations cause increased transcriptional activity as tested on the BCL6 promoter. The analysis of the N-terminal MEF2B crystal structure, upon mapping the mutated residues, predicted that these mutations may interfere with the ability of MEF2B to heterodimerize with the CABIN1 co-repressor. Indeed, we showed that these MEF2B mutant proteins fail to bind CABIN1 and are resistant to its transrepressive activity. Conversely, C-terminal MEF2B mutations lead to truncated MEF2B proteins lacking the domains responsive to two independent post-transcriptional modifications, namely PKA-mediated phosphorylation and sumoylation. We showed that MEF2B is in fact phosphorylated by PKA and sumoylated in vivo, that both of these modifications lead to negative regulation of MEF2B transcriptional activity, and that lymphoma-associated C-terminal mutants fail to be negatively regulated by PKA-mediated phosphorylation and sumoylation. In summary, these results identify MEF2B as an upstream regulator of BCL6 and GC formation, which is required for lymphoma proliferation. Lymphoma-associated MEF2B mutations may contribute to lymphomagenesis, at least in part, by deregulating the expression of the BCL6 oncogene. Thus, targeting MEF2B may represent an alternative therapeutic approach to block BCL6 and cell proliferation in DLBCL and FL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Increased MYC gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma

Haematologica ◽  
2010 ◽  
Vol 95 (4) ◽  
pp. 597-603 ◽  
Author(s):  
C. J. Stasik ◽  
H. Nitta ◽  
W. Zhang ◽  
C. H. Mosher ◽  
J. R. Cook ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Cell Lymphoma ◽  
Gene Copy Number ◽  
B Cell Lymphoma ◽  
Gene Copy ◽  
Mrna Levels ◽  
Large B Cell Lymphoma ◽  
Myc Gene ◽  
Large B Cell

scholarly journals The Copy Number Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Christopher Rushton ◽  
Miguel Alcaide ◽  
Matthew Cheung ◽  
Neil R Michaud ◽  
Scott Daigle ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Treatment Resistance ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Liquid Biopsies ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Introduction Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) are treated with standard frontline immunochemotherapy (R-CHOP). However, for cases where R-CHOP fails (relapsed-refractory DLBCL, rrDLBCL), prognosis is extremely poor, with 2-year overall survival of 20-40%. The successful development of new therapies may be hampered by our limited understanding of the genetic and molecular mechanisms underpinning treatment resistance. For example, recent data from our group has highlighted novel mutations that emerge following treatment with R-CHOP. The contribution of copy-number variations (CNVs) towards treatment resistance has not yet been thoroughly explored. A more complete characterization of these genetic alterations may lead to new prognostic biomarkers or treatment strategies. Methods We analyzed exome sequencing data from 59 rrDLBCL cases derived from either tissue biopsies or liquid biopsies collected after relapse, including both unpublished and previously published cases (Schmitz et al. (2018) NEJM 378:1396-1407 and Morin et al. (2016) Clin Can Res 22(9)). We separately performed low-pass whole-genome sequencing (lpWGS, 0.1-1x coverage) on 45 rrDLBCL liquid biopsies with ctDNA levels insufficient for exome-based analysis, for a total of 104 cases with copy-number information. We identified CNVs from exome and lpWGS data using Sequenza and ichorCNA, respectively. Next, we identified significant peaks of recurrent gains and losses using GISTIC2. Comparison of these peaks to CNVs in a previously published diagnostic DLBCL cohort (Schmitz et al. (2018) NEJM 378:1396-1407) enabled the identification of events that were significantly more prevalent in rrDLBCL. Results Overall, the landscape of CNVs in rrDLBCL is reminiscent of diagnostic DLBCL, with recurrent amplifications of chromosome 7 (43/104, 41.3%) and 18q (42/104, 40.4%) and recurrent deletions of 6q (25/104, 24.0%) and 17p13 (39/104, 37.5%). We identified nine regions enriched for recurrent amplifications or deletions among rrDLBCLs. These include deletions of 17p13.1 (20.4% in diagnostic biopsies vs 41.3% of rrDLBCLs, q=8.53x10-5) and recurrent amplifications of 8q24 (18.5% vs 42.3%, q=5.72x10-7) and 7p22 (27.2% vs 57.9%, q=6.29x10-8). Many of these peaks represent focal events that are exceedingly rare in diagnostic DLBCL and do not contain established lymphoma-associated genes, including amplifications affecting 700kb of 6p11.2 (2.03% vs 7.69%, q=0.0178) and 500kb of 19p13.3 (6.7% vs 31.7%, q=9.99x10-10). Notably, the 6p11.2 amplifications were associated with inferior progression-free survival following R-CHOP (p=0.02), with most tumors harboring this alteration relapsing within 12 months. We also identified a novel, recurrent deletion affecting a 20mb region of 5q (2.78% vs 10.6%, q=0.00604) which was significantly deleted in rrDLBCL. For tumors with additional samples collected prior to R-CHOP and following salvage therapy, deletions of 5q appeared to emerge following frontline therapy and persisted after subsequent treatments, suggesting they may contribute to treatment resistance. Discussion The 17p13.1 deletion enriched in rrDLBCL encompasses TP53, which is a common target of somatic point mutations in rrDLBCL and associated with inferior treatment outcomes. The amplification of 8q24 and 7p22 include MYC and GNA12/CARD11, respectively, although these large events encompass numerous additional genes which may be the target of such events. Curiously, the focal 6p11.2 amplification only overlaps a handful of genes including miR_598, which has been predicted to target CD27 and CD38 and whose expression is upregulated in B-cell cell lines (Lawrie et al. (2008) Leukemia 22:1440-2446). Further investigation and validation of these events and their corresponding targets will provide insight into the biology of rrDLBCL and may reveal novel therapeutic targets. Disclosures Michaud: Epizyme: Current Employment. Daigle:Epizyme: Current Employment. Jain:Kite/Gilead: Consultancy; Novartis: Consultancy. Kuruvilla:Merck: Consultancy, Honoraria; Bristol-Myers Squibb Company: Consultancy; Celgene Corporation: Honoraria; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; AbbVie: Consultancy; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria; Antengene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; TG Therapeutics: Honoraria. Crump:Servier: Consultancy; Roche: Consultancy; Kite/Gilead: Consultancy. Assouline:BeiGene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Steidl:Juno Therapeutics: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy; Bayer: Consultancy; Curis Inc: Consultancy. Johnson:AbbVie: Research Funding; Roche/Genentech, Merck: Honoraria; Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie: Consultancy. Scott:NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Janssen: Consultancy, Research Funding; Roche/Genentech: Research Funding; NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Celgene: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Morin:Celgene: Consultancy.

scholarly journals Identification BCL6 and miR-30 family associating with Ibrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma

2021 ◽  
Vol 38 (4) ◽  
Author(s):  
Jiazheng Li ◽  
Yan Huang ◽  
Yun Zhang ◽  
Jingjing Wen ◽  
Yanxin Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Venn Diagram ◽  
Potential Candidate ◽  
Large B Cell Lymphoma ◽  
Ibrutinib Resistance ◽  
Large B Cell ◽  
Geo Database

AbstractIbrutinib has clear efficacy for activated B-cell-like diffuse large B cell lymphoma (ABC-DLBCL) in previous clinical researches. However, the resistance of Ibrutinib has limited its therapeutic benefit and the potential mechanism remains unclear. This study was aimed to identify potential candidate genes and miRNA targets to overcome Ibrutinib resistance in ABC-DLBCL. First, two expression profiles were downloaded from the GEO database, which used to identify the DEGs related to Ibrutinib resistance in ABC-DLBCL cell lines by GEO2R analysis separately. And the common DEGs were obtained though Venn diagram. Then Gene ontology (GO) and pathway enrichment analysis were conducted by DAVID database. From STRING database, BCL6, IL10, IL2RB, IRF4, CD80, PRDM1and GZMB were determined to be the hub genes by protein–protein interaction (PPI) network. Through miRNA-mRNA targeting network, we found that BCL6, IRF4, CD80, and PRDM1 were common target genes of miR-30 family. The cBioPortal database showed that BCL6 had the highest level of genetic alterations among DLBCL. In addition, another expression profile from GEO database showed that BCL6 was significantly high expression in no responsive patients after Ibrutinib treatment, and the receiver operating characteristic (ROC) curve which was used to evaluate the relationship between BCL6 expression and its effect was 0.67. MTT assay showed that treatment with FX1 (a BCL6 inhibitor) can enhance the sensitivity of Ibrutinib in C481S BTK HBL-1 cells. The results suggested that BCL6 and miR-30 family maybe associate with Ibrutinib resistance in ABC-DLBCL.

Anaplastic Variant of Diffuse Large B-cell Lymphoma Displays Intricate Genetic Alterations and Distinct Biological Features

2017 ◽  
Vol 41 (10) ◽  
pp. 1322-1332 ◽  
Author(s):  
Mingyang Li ◽  
Yixiong Liu ◽  
Yingmei Wang ◽  
Gang Chen ◽  
Qiongrong Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Biological Features ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma

Blood ◽  
2021 ◽  
Author(s):  
Wendan Xu ◽  
Philipp Berning ◽  
Georg Lenz
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
B Cell Receptor ◽  
Special Focus ◽  
Large B Cell Lymphoma ◽  
Bcr Signaling ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category comprising distinct molecular subtypes characterized by diverse genetic aberrations that dictate patient outcome. As roughly one-third of DLBCL patients are not cured by current standard chemo-immunotherapy a better understanding of the molecular pathogenesis is warranted to improve outcome. B-cell receptor (BCR) signaling is crucial for the development, growth and survival of both normal and a substantial fraction of malignant B-cells. Various analyses revealed genetic alterations of central components of the BCR or its downstream signaling effectors in some subtypes of DLBCL. Thus, BCR signaling and the downstream NF-κB and PI3K cascades have been proposed as potential targets for the treatment of DLBCL patients. As one of the main effectors of BCR activation, PI3K mediated signals play a crucial role in the pathogenesis and survival of DLBCL. In this review, we summarize our current understanding of BCR signaling with a special focus on the PI3K pathway in DLBCL and how to utilize this knowledge therapeutically.

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