B cells gone rogue: the intersection of diffuse large B cell lymphoma and autoimmune disease

Primary extranodal malignant lymphoma of the thyroid is a rare entity composed of mostly neoplastic transformation of germinal center-like B cells (GCB) or memory B cells. Other B-cell-type malignancies arising primarily in the thyroid have rarely been described. Immunohistochemical examination of autopsied primary malignant lymphoma of the thyroid in an 83-year-old Japanese female revealed the presence of a non-GCB subtype of diffuse large B-cell lymphoma (DLBCL) without the typical codon 206 or 265 missense mutation of MYD88. The lack of the highly oncogenic MYD88 gene mutation, frequently observed in DLBCL of the activated B-cell (ABC) subtype, and the detection of an extremely aggressive yet local clinical phenotype demonstrated that the present case was an exceptional entity of the type3 (non-GCB and non-ABC) subtype.

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Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Blood ◽

10.1182/blood-2009-06-225839 ◽

2009 ◽

Vol 114 (20) ◽

pp. 4503-4506 ◽

Cited By ~ 81

Author(s):

Anja Mottok ◽

Christoph Renné ◽

Marc Seifert ◽

Elsie Oppermann ◽

Wolf Bechstein ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Rare Mutations ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Follicular Lymphomas ◽

Large B Cell

Abstract STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare mutations were observed in Burkitt lymphoma, plasmacytoma, and mantle cell lymphoma but not in tumors of a non–B-cell origin. Mutations in single-sorted germinal center B cells were infrequent relative to other genes mutated as byproducts of normal SHM, indicating that SOCS1 inactivation in primary mediastinal large B-cell lymphoma, HL, diffuse large B-cell lymphoma, and follicular lymphoma is frequently the result of aberrant SHM.

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Effect of siRNA interference of ubiquitin-specific protease 9X on apoptosis and growth of diffuse large B cell lymphoma cell line

Materials Express ◽

10.1166/mex.2020.1653 ◽

2020 ◽

Vol 10 (3) ◽

pp. 446-453

Author(s):

Wei Peng ◽

Meizuo Zhong ◽

Youhong Tang

Keyword(s):

B Cells ◽

Protein Expression ◽

B Cell ◽

Cell Apoptosis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Specific Protease ◽

Sirna Interference ◽

Large B Cell

Ubiquitin-specific protease 9X (USP9X) is crucial in the diagnosis and treatment of many tumor types, but its role in Diffuse Large B Cell Lymphoma (DLBCL) has not been determined. The current study aimed to examine the effects of RNA interference on USP9X expression, and subsequently on the bioactivity of DLBCL Farage and Pfeiffer cells. There were two groups in the study: USP9X-siRNA and NC. USP9X siRNA was transiently transferred into DLBCL cells by Cationic liposome. The total RNA was extracted using Fe2O3 and was retrieved into the DNA using the MagBeads Total RNA Extraction Kit. The protein expression of USP9X in Farage, Pfeiffer, and normal human B cell line at the cellular level was observed by Western blot. The Farage and Pfeiffer cells were infected with USP9X-siRNA. Cell apoptosis and cell growth viability were analyzed by flow cytometry and CCK8, Mcl-1 protein, a potential target of USP9X, and apoptosis factor proteins (such as Bak, Cytochrome C, Caspase 3, Caspase 8, PARP) were detected by Western blot after siRNA interference. The results showed that the protein expression of USP9X in malignant B cells was four times higher than that of the normal B cells. Inhibition of USP9X reduced the Mcl-1 activity, and increased the caspase-3, Bak and Cytochrome C activity. In the malignant B cells, Mcl-1 and Bak were binding in vivo; Bak was a new partner of Mcl-1. Inhibition of USP9X reduced cell proliferation and increased apoptosis. The expression of USP9X is upregulated in Diffuse large B cell lymphoma cells, Farage, and Pfeiffer. Inhibition expression of USP9X may induce cell apoptosis, inhibit cell growth, and downregulate Mcl-1 protein expression in Diffuse large B cell lymphoma cells, Farage, and Pfeiffer. USP9X has the ability in regulating cell apoptosis.

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Aberrant Somatic Hypermutation Targets an Extensive Set of Genes in Diffuse Large B-Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.1528.1528 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1528-1528 ◽

Cited By ~ 1

Author(s):

Laura Pasqualucci ◽

Roberta Guglielmino ◽

Sami N. Malek ◽

Urban Novak ◽

Mara Compagno ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lines ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Chromosomal Translocations ◽

Total N ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Genomic instability is a driving force in tumor development that can be achieved by a variety of mechanisms, such as defective chromosome segregation or inactivation of the DNA mismatch repair pathway. Although B-cell lymphomas are associated with chromosomal translocations deregulating oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has long not been described. We have reported that the somatic hypermutation process (SHM), which normally targets the immunoglobulin variable region (IgV) and BCL6 genes in germinal center (GC) B-cells, functions aberrantly in >50% of diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell non-Hodgkin lymphoma (Pasqualucci et al., Nature412:341, 2001). As a consequence, multiple somatic mutations are introduced into the 5′ region of genes that do not represent physiologic SHM targets, including known proto-oncogenes such as PIM1, PAX5, RhoH/TTF and cMYC. To further define the extent of this phenomenon, termed aberrant somatic hypermutation (ASHM), and to identify additional hypermutated loci of possible pathogenetic significance in DLBCL, we screened 113 genes for the presence of mutations affecting their 5′ sequences (≥1.3 Kb from the transcription start site, the target region for SHM) in 10 DLBCL cell lines. Fifteen genes (13.3%) were found to harbor a significant number of mutations (p<0.05), with 70% of the cell lines being mutated in 7 or more genes; among these, six B-cell specific loci -BCL7A, CIITA, IRF4, LRMP, NCOA3 and SIAT1- carried 9–53 mutational events distributed in 20 to 70% of the cases, corresponding to an overall mutation frequency of 0.032–0.15% (frequency in the mutated cases: 0.07–0.25%). The same genes were found hypermutated in a panel of 20 primary DLBCL biopsies, which displayed an overall mutation load of 7 to 45 distinct events/gene (total N=125). Mutations were of somatic origin, independent of chromosomal translocations to the Ig loci and were restricted to the first 1.5–2 Kb from the promoter. In addition, analogous to previously identified SHM and ASHM targets, the mutations exhibited characteristic features, including a bias for transitions over transversions, preferential hotspot (RGYW/WRCY motifs) targeting, and higher frequencies at G:C pairs. However, in contrast to physiologic SHM targets such as IgV and BCL6, none of the 4 newly identified hypermutated genes that have been analyzed so far (BCL7A, CIITA, SIAT1, LRMP) displayed significant levels of mutations in purified normal GC B-cells as well as in other B-cell malignancies. This finding indicates that these genes represent aberrant hypermutation targets resulting from a tumor-associated malfunction, possibly a loss of target specificity of the physiologic SHM process. Considering previous results and the present survey, 17 (13%) out of 130 genes investigated have been found involved in ASHM, suggesting that this aberrant activity may involve an extensive set of target genes in DLBCL. Since the mutations affect both regulatory and coding sequences of the targeted genes, aberrant SHM may represent a major contributor to the pathogenesis of this disease and may explain in part its phenotypic and clinical heterogeneity.

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Preferential Acquision of N-Glycosylation Sites in the VDJ Region in Germinal Center B-Cell-Like Difusse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.1589.1589 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1589-1589 ◽

Cited By ~ 1

Author(s):

Miguel Alcoceba ◽

Elena Sebastián ◽

Ana Balanzategui ◽

Luis Marín ◽

Santiago Montes-Moreno ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Marginal Zone ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Marginal Zone Lymphoma ◽

Large B Cell Lymphoma ◽

Glycosylation Sites ◽

Large B Cell

Abstract Abstract 1589 Introduction: Acquired potentially N-glycosylation sites are produced by somatic hypermutation (SHM) in the immunoglobulin (Ig) variable region. This phenomenon is produced in ∼9% of normal B-cells and seems to be related to certain B-cell lymphoproliferative disorders (B-LPDs) such as follicular lymphoma (FL, 79%), endemic Burkitt lymphoma (BL, 82%) and diffuse large B-cell lymphoma (DLBCL, 41%). These data suggest that new potential N-glycosylation sites could be related to germinal center B (GCB)-LPDs. By contrast, in other B-LPDs, such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), MALT lymphoma, Waldenström macroglobulinemia (WM) or multiple myeloma (MM), these modifications have not been analyzed in deep. Aims: To evaluate the acquisition of potential N-glycosylation sites in B-LPDs, including immunohystochemical DLBCL subtypes (GCB and non-GCB) and specific non-GCB-LPDs, such as hairy cell leukemia (HCL), splenic marginal-zone lymphoma (SMZL), CLL, MCL, ocular extranodal marginal zone lymphoma (OAEMZL), MM and WM. Patients: A total of 953 sequences (203 from our group and 750 previously published sequences) of B-LPDs were included. Diagnosis distribution was as follows: DLBCL (n=235), MCL (n=235), CLL (n=166), MM (n=96), OAEMZL (n=82), SMZL (n=68), WM (n=38) and HCL (n=33). Methods: Acquired N-glycosylation sites were counted according to the sequence Asn-X-Ser/Thr, where X could be any amino acid except Pro. Natural motifs in germline sequences of IGHV1–08, IGHV4–34 e IGHV-5a were not considered. Fisher test was used to perform comparisons between groups. To distinguish DLBCL biological subtypes (GCB and non-GCB DLBCL), Hans' algorithm was used. Results: A total of 83 out of the 235 DLBCL cases acquired at least a new N-glycosylation site, a higher value than in normal B-cells (35% vs. 9%, p<0.0001). Higher incidence of these motifs in the group of GCB as compared to non-GCB DLBCL were observed (52% vs. 20%, p<0.0001). Those cases diagnosed of HCL, CLL, MCL, MM, WM, OAEMZL and SMZL presented a reduced number of new N-glycosylation sites, showing similar values than normal B-cells (range 3–18%, p=ns). Conclusions: We described for the first time the pattern of N-glycosylation in HCL, SMZL, OAEMZL and in the immunohystochemical DLBCL subtypes, where the GCB-DLBCL showed a higher number of new N-glycosylation sites with respect to non-GCB DLBCL and other non-GCB-LPDs. The presence of novel N-glycosylation sites in FL, BL and in GCB-DLBCL strongly suggests that these motifs are characteristic of the germinal center B-LPDs. Disclosures: No relevant conflicts of interest to declare.

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Characterizing Autoimmune Disease-associated Diffuse Large B-cell Lymphoma in a SEER–Medicare Cohort

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2017.11.009 ◽

2018 ◽

Vol 18 (2) ◽

pp. e115-e121 ◽

Cited By ~ 5

Author(s):

Jean L. Koff ◽

Ashish Rai ◽

Christopher R. Flowers

Keyword(s):

Autoimmune Disease ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Anti-CD19 monoclonal antibodies for the treatment of relapsed or refractory B-cell malignancies: a narrative review with focus on diffuse large B-cell lymphoma

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-021-03833-x ◽

2021 ◽

Author(s):

Pier Luigi Zinzani ◽

Giorgio Minotti

Keyword(s):

Monoclonal Antibodies ◽

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Leukaemia ◽

Antibody Drug Conjugate ◽

B Cell Malignancies ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Purpose CD19 is a cell surface protein that is found on both healthy and malignant B cells. Accordingly, it has become an important target for novel treatments for non-Hodgkin lymphomas and B-cell leukaemia. Three anti-CD19 monoclonal antibodies with distinct mechanisms of action have been developed for the treatment of B-cell malignancies. Methods We reviewed the preclinical and clinical data on the development of the newly approved anti-CD19 monoclonal antibodies blinatumomab, tafasitamab and loncastuximab tesirine, and consider their place in the treatment of relapsed or refractory B-cell malignancies. Results Blinatumomab is a bispecific T-cell engager that binds to both CD19 on B cells and CD3 on T cells, facilitating antibody-dependent cytotoxicity. Blinatumomab significantly prolongs overall survival in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia, although cytokine release syndrome and severe neurotoxicity may necessitate discontinuation. Tafasitamab, which has modified anti-CD19 Fab and Fc regions, has significantly enhanced affinity for both CD19 and effector cell receptors compared with unmodified anti-CD19. In L-MIND, tafasitamab plus lenalidomide provided an overall response rate (ORR) of 57.5% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients non-transplant eligible. Loncastuximab tesirine is an antibody–drug conjugate that has been studied as monotherapy and in combination with ibrutinib in 3L + relapsed or refractory DLBCL. The ORR was 48.3% in a phase II trial of loncastuximab tesirine. The optimal place of anti-CD19 monoclonal antibodies in therapy has yet to be determined, but the prospect of improved outcomes for at least some patients with treatment-resistant B-cell malignancies appears likely, particularly in those with limited therapeutic options and poor prognosis.

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Genomic and Transcriptional Characterization of Primary Mediastinal Large B Cell Lymphoma

Blood ◽

10.1182/blood-2021-149745 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2398-2398

Author(s):

Rebecca J Leeman-Neill ◽

Devang Thakkar ◽

Sarah L. Ondrejka ◽

Eric D. Hsi ◽

Amy Chadburn ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Research Funding ◽

Immune Escape ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Dna And Rna ◽

Large B Cell Lymphoma ◽

Recurrent Mutations ◽

Large B Cell

Abstract Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare non-Hodgkin lymphoma subtype that occurs predominantly in young adults, with an overall favorable prognosis. The cell of origin is presumed to be thymic medullary B-cells and the gene expression profile of PMBL is similar to classic Hodgkin lymphoma. Recent studies have begun unravelling the genomic alterations underlying PMBL. Frequent, recurrent mutations (e.g. B2M, TNFAIP3, SOCS1, STAT6, GNA13) have been reported, but most of the studies have analyzed a small number of cases. To gain further insights into disease biology, we recruited 63 cases of PMBL as part of the Atlas of Blood Cancer Genomes (ABC-G) initiative, a consortium consisting of 25 institutions. Methods: Formalin-fixed paraffin-embedded (FFPE) biopsies and clinical data were collected. All cases were subjected to centralized review by an experienced panel of hematopathologists to ensure accurate diagnosis. Whole-exome DNA and RNA sequencing was performed using the Illumina platform and the DNA and RNA reads aligned to the GRCh38 genome and transcriptome respectively. Exonic variants were filtered using a set of paired normal samples and population-based databases to identify putative driver mutations, which were then aggregated at the gene level. Mutational analysis was performed on 56 samples that passed quality filtering and expression analysis on 45 samples. RNAseq data was normalized using DESeq2. Results: The cohort included samples from 16 males and 24 females, with a median age of 33 years (range 16 - 72) at the time of diagnosis. The majority of patients were treated with R-CHOP (47%) or R-EPOCH (43%), with 93% of patients surviving through the end of follow-up (median follow-up: 60.1 months). Besides the known recurrent mutations involving the JAK-STAT (STAT6 -21%, SOCS1 - 26%), NFKB (TNFAIP3 - 27%, NFKB1A - 7%), immune escape (B2M - 20%, LTB - 11%, IRF8 - 9%, IRF4 -9%), and chromatin modification (ZNF217 - 16%, CREBBP - 11%, KMT2D -11%) pathways , we discovered recurrent somatic variants in novel candidate driver genes in this disease, including NOTCH4 (7%), DICER1 (11%), MCL1 (7%), amongst others. EZH2, EP300, and XPO1 mutations were not detected. CIITA mutations and fusions were observed in 14% and 11% of cases, respectively, with novel partner genes (IGHA2, IGHG1, CDC6) detected in 67% of the fusion positive cases. Copy number alterations included gains at 2p16.1 (REL - 20%) and 9p24.2 (JAK2/PDL1/PDL2 - 24%), as well as loci not previously implicated in PMBL, 8q24.3 and 9q34.3 (each in 20%). Of note, CIITA alterations and 9p24 gains were virtually mutually exclusive, highlighting diverse mechanisms of immune escape in this entity. The transcriptomes of cases harboring CIITA alterations demonstrated differential enrichment of genes involved in protein glycosylation. The PMBLs in our series showed significant enrichment of the reported PMBL genetic classifier score, compared to nodal diffuse large B cell lymphoma (DLBCL) (p=0.0003). Finally, the gene expression profile of thymic B cells was more similar to that of PMBL than nodal DLBCL (p=0.0144). Conclusions: Our study, representing one of the largest comprehensive genomic and transcriptomic analyses of PMBL, expands the mutational landscape of PMBL, provides evidence for biologically distinct disease subsets and suggests an origin of PMBLs from thymic B-cells. Disclosures Hsi: AbbVie: Research Funding; Eli Lilly: Research Funding; Cytomx: Honoraria; Seattle Genetics: Honoraria. McKinney: BTG: Consultancy; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; Genetech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy; Verastem: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau. Jaye: Stemline Therapeutics: Honoraria. Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

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

Blood ◽

10.1182/blood.v120.21.1284.1284 ◽

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.

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