scholarly journals The uracil-DNA glycosylase UNG protects the fitness of normal and cancer B cells expressing AID

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Shiva Safavi ◽  
Ariane Larouche ◽  
Astrid Zahn ◽  
Anne-Marie Patenaude ◽  
Diana Domanska ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Suppressor ◽  
B Cell ◽  
Cell Subset ◽  
B Cell Lymphoma ◽  
Cell Populations ◽  
Dna Damage And Repair ◽  
Gene Diversification ◽  
Activation Induced Deaminase

Abstract In B lymphocytes, the uracil N-glycosylase (UNG) excises genomic uracils made by activation-induced deaminase (AID), thus underpinning antibody gene diversification and oncogenic chromosomal translocations, but also initiating faithful DNA repair. Ung−/− mice develop B-cell lymphoma (BCL). However, since UNG has anti- and pro-oncogenic activities, its tumor suppressor relevance is unclear. Moreover, how the constant DNA damage and repair caused by the AID and UNG interplay affects B-cell fitness and thereby the dynamics of cell populations in vivo is unknown. Here, we show that UNG specifically protects the fitness of germinal center B cells, which express AID, and not of any other B-cell subset, coincident with AID-induced telomere damage activating p53-dependent checkpoints. Consistent with AID expression being detrimental in UNG-deficient B cells, Ung−/− mice develop BCL originating from activated B cells but lose AID expression in the established tumor. Accordingly, we find that UNG is rarely lost in human BCL. The fitness preservation activity of UNG contingent to AID expression was confirmed in a B-cell leukemia model. Hence, UNG, typically considered a tumor suppressor, acquires tumor-enabling activity in cancer cell populations that express AID by protecting cell fitness.

Blimp1 Is a Tumor Suppressor Gene in Diffuse Large B Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 446-446 ◽  
Author(s):  
Jonathan Mandelbaum ◽  
Govind Bhagat ◽  
Tongwei Mo ◽  
Alexander Tarakhovsky ◽  
Laura Pasqualucci ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Gene ◽  
B Cell Lymphoma ◽  
Suppressor Gene ◽  
Cell Phenotype ◽  
B Cell Differentiation

Abstract Abstract 446 The PRDM1/ BLIMP1 gene encodes a zinc finger transcriptional repressor that is expressed in a subset of germinal center (GC) B cells and in all plasma cells, and is required for terminal B cell differentiation. The BLIMP1 locus is biallelically inactivated by structural alterations in approximately one third of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL) (Pasqualucci et al, J Exp Med 2006). Moreover, the expression of the Blimp1 protein is absent in up to 80% of ABC-DLBCL due to alternative genetic and epigenetic mechanisms. These findings suggest that BLIMP1 may function as a tumor suppressor gene whose loss may contribute to the pathogenesis of this lymphoma type by blocking terminal B cell differentiation. To investigate the role of BLIMP1 inactivation in lymphomagenesis in vivo, we tested whether conditional deletion of the Blimp1 gene in mouse B cells can promote the growth of lymphomas recapitulating the features of ABC-DLBCL. Toward this end, a mouse model carrying a loxP-flanked exon 5 of the Blimp1 gene that can be deleted by Cre-mediated recombination (Ohinata et al, Nature 2005) was crossed with a CD19-Cre deletor strain, expressing the Cre recombinase in all B cells. The resulting mice were monitored for tumor development and survival. Consistent with previous observations in a similar model (Shapiro-Shelef et al, Immunity 2003), Blimp1 conditional knockout (Blimp1CD19KO) mice showed a severe impairment in the generation of CD138+ plasma cells and had decreased serum immunoglobulin levels of all isotypes, together with a two-fold increase in the number of PNAhiCD95+ GC B cells. Over time, significantly reduced survival was observed in the Blimp1CD19KO cohort, with only 27% of the animals being alive at 15 months of age (LogRank p value<0.0001). Macroscopic and flow cytometric analysis of the lymphoid compartments revealed the presence of splenomegaly in 32/38 (84%) Blimp1CD19KO, as compared to 1/25 (4%) age-matched wildtype (WT) littermates, and a significant increase in IgM+IgD-CD21+CD23lo splenic B cells, indicative of marginal zone B cell expansion. In addition, 79% (n=30/38) of Blimp1CD19KO mice showed markedly hyperplastic bronchus-associated lymphoid tissue (BALT). Notably, between 10 and 16 months of age 34% (13/38) of these animals developed clonal lymphoproliferative disorders with a mature B cell phenotype (B220+Pax5+) and histologic features of DLBCL (n=6) or less aggressive lymphoid proliferations (LPD: n=6; marginal zone lymphoma: n=1), in contrast with 1/27 heterozygous and 0/25 WT animals. Sequencing analysis of the rearranged immunoglobulin variable region genes in lymphoma biopsies revealed the presence of somatic mutations in 6/8 samples investigated, demonstrating their origin from a GC-experienced B cell. Moreover, immunohistochemical staining for Bcl6 and Irf4 documented a late-GC “activated” B cell phenotype (Bcl6-Irf4+) in all tumors tested (n=4), consistent with the expansion of cells that had been committed to plasma cell differentiation. These data demonstrate that Blimp1 is a bona-fide tumor suppressor gene whose B-cell specific inactivation in vivo promotes the development of lymphomas sharing features of the human ABC-DLBCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals UNG protects B cells from AID-induced telomere loss

2016 ◽  
Vol 213 (11) ◽  
pp. 2459-2472 ◽  
Author(s):  
Elena M. Cortizas ◽  
Astrid Zahn ◽  
Shiva Safavi ◽  
Joseph A. Reed ◽  
Francisco Vega ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Excision Repair ◽  
B Cell Lymphoma ◽  
Gene Diversification ◽  
Telomere Loss ◽  
Activation Induced Deaminase ◽  
Safe Mechanism ◽  
Fail Safe

Activation-induced deaminase (AID) initiates antibody gene diversification by creating G:U mismatches in the immunoglobulin loci. However, AID also deaminates nonimmunoglobulin genes, and failure to faithfully repair these off-target lesions can cause B cell lymphoma. In this study, we identify a mechanism by which processing of G:U produced by AID at the telomeres can eliminate B cells at risk of genomic instability. We show that telomeres are off-target substrates of AID and that B cell proliferation depends on protective repair by uracil-DNA glycosylase (UNG). In contrast, in the absence of UNG activity, deleterious processing by mismatch repair leads to telomere loss and defective cell proliferation. Indeed, we show that UNG deficiency reduces B cell clonal expansion in the germinal center in mice and blocks the proliferation of tumor B cells expressing AID. We propose that AID-induced damage at telomeres acts as a fail-safe mechanism to limit the tumor promoting activity of AID when it overwhelms uracil excision repair.

CDDO and CDDO-Im Reduce Tumor Burden in a Transgenic Mouse Model of CLL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3477-3477
Author(s):  
Juan M. Zapata ◽  
Christina L. Kress ◽  
Marina Konopleva ◽  
Maryla Krajewska ◽  
Mark Hyer ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Tumor Burden ◽  
Leukemic Cells ◽  
Medium Size ◽  
Control Group

Abstract Transgenic mice over-expressing in B lymphocytes both Bcl-2 and a TRAF2 mutant lacking the N-terminal RING and zinc finger domains (TRAF2DN), which mimics TRAF1, develop small B cell lymphoma and leukemia that have remarkably similar characteristics to human chronic lymphocytic leukemia (CLL). TRAF2DN/Bcl-2 mice develop over time leukemia, severe splenomegaly, and lymphadenopathy, which are associated with monoclonal and oligoclonal B cell neoplasms. The lifespan of TRAF2DN/Bcl-2 mice is markedly reduced compared to Bcl-2 and TRAF2DN single transgenics or wild-type littermates. The expanded B cell population in the blood of leukemic TRAF2DN/Bcl-2 double transgenic mice is primarily comprised of small-medium size, non-cycling B220M/IgMH/IgDL/CD21L/CD23−/CD11b+/CD5+ cells that were Bcl-6 negative, consistent with a B-1 phenotype, closely resembling their human CLL counterparts. Indeed, these B cells showed comparable proliferation rates to normal B-cells, but exhibited markedly increased survival and were resistant to apoptosis induced by chemotherapeutic agents and glucocorticoids. We studied the effects of synthetic triterpenoid 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid (CDDO) and its imidazolide derivative (CDDO-Im) on cultured B-cells from the TRAF2DN/Bcl-2 transgenic mice. Both CDDO and CDDO-Im efficiently induced apoptosis of these cells in vitro, although CDDO-Im was approximately 10-times more potent than CDDO (LD50: 0.35μM CDDO-Im vs 3.8 μM CDDO). To study the effect of CDDO and CDDO-Im in vivo, groups of TRAF2DN/Bcl-2 mice that had developed leukemia were injected i.v. with liposomes alone or liposomes containing either CDDO or CDDO-Im, at a dose of 20 mg/kg/day. Each mouse received a total of nine injections administered over a period of 22 days. The concentration of B cells in the blood of these mice was monitored daily after each injection, using a mini-FACS (Guava Technologies, Inc.). CDDO-treated mice showed a steady reduction in the number of leukemic cells in blood during the treatment and this tendency was maintained 10 days after the last treatment. In contrast, CDDO-Im treated mice showed a striking increase in the concentration of B cells in blood (B220+ events) immediately after the first inoculation. One mouse of this group died after the first injection, and 2 more mice died after 5 injections. Only 2 mice treated with CDDO-Im survived the full treatment, showing a striking reduction of leukemic cells in blood by the end of the treatment. Administration of empty liposomes had no inhibitory effect on the leukemia, and mice in this control group had massive splenomegaly (1431±323 mg; n=3) and severe disseminated lymphadenopathy. In contrast, CDDO-treated mice had less severe splenomegaly (938±234; n=4) but still had severe lymphadenopathy. CDDO-Im treated mice showed a dramatic reduction in the spleen size that was evident also in those mice that died after 5 injections (474±185 mg; n=4) and had no signs of lymphadenopathy. Although preliminary, these results indicate that in vivo administration of CDDO and CDDO-Im reduced the tumor burden in a transgenic model of CLL, and illustrate the potential of triterpenoids as single agents for the treatment of CLL.

Protein Signature of LMP1 Signaling in PTLDs Identifies and Mimics Inter/Perifollicular CD30+ EBV− B Blasts.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3251-3251
Author(s):  
Rita Shaknovich ◽  
Katia Basso ◽  
Govind Bhagat ◽  
Bachir Alobeid ◽  
Giorgio Cattoretti
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cellular Transformation ◽  
Cell Types ◽  
Marginal Zone B Cells ◽  
Latently Infected ◽  
Protein Signature

Abstract EBV-associated B-cell Post-Transpant Lymphoproliferative Disorders (PTLDs) represent a diverse group of lesions morphologically, in clinical presentation and behaviour, ranging from early reversible lesions to monomorphic aggressive lymphomas. Polymorphic cases, which represent the focus of our analysis, contain a mixture of cells in various EBV latency stages, defined by EBNA1, EBNA2 and LMP1 immunostaining. LMP1 is a key viral protein for cellular transformation and, analogously to CD40, engages TNF Receptor Associated Proteins and activates NF-kB and NF-kB-responsive genes. We analyzed the protein signature of LMP1 in PTLDs and non-PTLD tonsils by double staining for LMP1, CD30, CD20, Pax5 and signaling molecules. A remarkably conserved set of proteins, associated with LMP1/CD40 signaling and NF-kB activation is expressed both in the EBV-infected lymphoid population in polymorphic PTLDs and in a normal B-cell subset(s) in reactive tonsils. These proteins include highly expressed CD30, JunB, nuclear cRel, TRAF-1, Bcl-XL, MUM1, CCL22 and downregulated BCL6 and CD10. We observed that EBV infection, possibly through LMP1 and LMP2A signaling, results in varioius degrees of differentiation within the neoplastic clone. EBER+ terminally differentiated mucosa-associated IRTA-1+ marginal zone B-cells and CD138+ plasma cells were identified in most cases, including control post-transplant tonsils with no overt disease. We document for the first time in situ, in-vivo evidence of EBV latently infected post-Germinal Center B cells of marginal and plasma cell types in PTLDs. Polymorphic PTLD cases represent EBV-induced expansion of B cells, mimicking CD40L-like activated Peri/Interfollicular CD30+ normal B-cells.

Pathologic Co-Expression and Physical Interaction of c-MYC and BCL6 in B-Cell Lymphomas.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2-2 ◽  
Author(s):  
Masumichi Saito ◽  
Ryan T. Phan ◽  
Herbert C. Morse ◽  
Laura Pasqualucci ◽  
Riccardo Dalla-Favera
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Transgenic Animals ◽  
Primary Lymphoma ◽  
Physical Interaction

Abstract Deregulated expression of the proto-oncogenes BCL6 and c-MYC caused by chromosomal translocation or somatic hypermutation is common in non-Hodgkin B cell lymphoma derived from germinal center (GC) B cells, including diffuse large cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Normal GC B cells express BCL6, whereas, surprisingly, they do not express c-MYC, suggesting that the expression of this oncogene in BL and DLBCL (20% of cases) is ectopic (Klein, U. et al. Proc Natl Acad Sci U S A100, 2639–2644, 2003). Here we report that c-MYC is absent in proliferating GC B cells because it is transcriptionally suppressed by BCL6, as demonstrated by the presence of specific BCL6 binding sites in the c-MYC promoter region and by chromatin immunoprecipitation experiments showing that BCL6 is bound to these sites in vivo. Thus, c-MYC escapes BCL6-mediated suppression in lymphoma leading to the co-expression of the two transcription factors, an event never observed in immunohistochemical and gene expression profile analysis of normal GC B cells. Surprisingly, co-immunoprecipitation experiments and in vitro binding experiments indicate that, when co-expressed, BCL6 and c-MYC are physically bound in a novel complex detectable in DLBCL and BL cell lines as well as in primary lymphoma cases. The formation of the BCL6/c-MYC complex has several significant functional consequences on the function of both c-MYC and BCL6: 1) a two fold, BCL6-binding dependent increase in c-MYC half-life, an event that has been shown to contribute to its oncogenic activation; 2) a synergistic increase in the ability of both BCL6 and c-MYC to suppress MIZ1-activated transcription of the p21CIP cell cycle arrest gene; 3) MYC-dependent inhibition of BCL6 acetylation by p300, an event that physiologically inactivates BCL6 via c-MYC-mediated recruitment of HDAC. Notably, the pathologic co-expression of c-MYC and BCL6 was shown to have pathologic consequences in vivo, since double transgenic BCL6/c-MYC mice display accelerated lymphoma development and the appearance of a novel GC-derived tumor phenotype not recognizable in single transgenic animals and containing the pathologic c-MYC/BCL6 complex. Thus, the pathologic co-expression and illegitimate physical interaction of BCL6 and c-MYC leads to an increase in the constitutive activity of both oncogenes. These results identify a novel mechanism of oncogenic function for BCL6 and c-MYC and a novel tumor-specific protein complex of potential therapeutic interest.

CD40 Ligand Activation Alters B Cell Migration to Secondary Lymphoid Organs.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 935-935
Author(s):  
Yvonne A. Efebera ◽  
Tahamtan Ahmadi ◽  
Amanda Flies ◽  
David H. Sherr
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Cd40 Ligand ◽  
Lymphoid Organs ◽  
Cell Populations ◽  
Secondary Lymphoid Organs ◽  
Activated B Cells

Abstract Background: An increased understanding of the requirements for antigen presentation has encouraged development of cell-based cancer vaccines. Trials using dendritic cells (DC) as antigen presenting cells (APC) for immunotherapy of several malignancies have shown considerable success. However, the difficulty in generating large numbers of DC required for these immunizations has led to the search for alternative APC. One such candidate is the CD40 ligand (CD40L)-activated B cell, populations of which can readily be expanded in vitro. To be an effective vehicle for antigen presentation to T cells, CD40L-activated B cells must be capable of migrating to secondary lymphoid organs. Therefore, CD40L-activated B cell migration following subcutaneous or intravenous injection was evaluated. Methods: Splenic B cells from GFP transgenic mice were activated with CD40L + IL-4 and expanded in vitro prior to i.v. or s.c. injection of 3–4 x 107 into C57BL/6 mice. Recipient mice were sacrificed 2 hrs or 1–14 days thereafter and the percentage of GFP+/B220+ B cells quantified in spleens and lymph nodes by flow cytometry. Localization of these cells within lymphoid organs was determined by immunohistochemistry. In some experiments, activated C57BL/6 B cells were labeled with carboxy fluorescein succinimidyl ester (CFSE) to evaluate cell growth in vivo. Results: Murine B cell populations were readily expanded by culture on CD40L-transfected L cells in the presence of IL-4. CD40L-activated B cells expressed high levels of CD80, CD86, and LFA-1 but decreased levels of L-selectin relative to naive cells. Following i.v. injection, activated B cells were detected in spleens and lymph nodes within 1 day. Peak concentrations of activated B cells were noted in spleens and lymph nodes on days 7 (4.8% of injected cells) and 10 (1.25% of injected cells) respectively, suggesting expansion of the activated B cell population in vivo. Naive B cells injected i.v. were detected within 1 day but their number declined precipitously thereafter. Following s.c. injection, peak levels of CD40L-activated B cells were noted on day 5 (spleens) and day 7 (lymph nodes). As determined by immunohistochemistry, both CD40L-activated and naïve B cells injected i.v. appeared in B cell regions of spleens and lymph nodes. While the kinetics of accumulation of CD40L-activated B cells injected s.c. or i.v. were similar, s.c. injected CD40L-activated B cells homed to the T cell regions of spleens and lymph nodes. CFSE experiments indicated that these activated B cells continue to grow in vivo. In contrast, naïve B cells injected s.c. only appeared in B cell regions. Conclusion: CD40L-activated B cell populations can readily be expanded in vitro, CD40L-activated B cells migrate to secondary lymphoid organs even when injected s.c., activated B cell populations expand in vivo, and s.c. injected, CD40L-activated B cells preferentially home to T cell regions of secondary lymphoid organs. These results suggest that this effective APC may serve as an important vehicle for delivery and presentation of exogenous (e.g. tumor) antigens to T cells in vivo.

scholarly journals KLF4 suppresses transformation of pre-B cells by ABL oncogenes

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 747-755 ◽  
Author(s):  
Michael G. Kharas ◽  
Isharat Yusuf ◽  
Vanessa M. Scarfone ◽  
Vincent W. Yang ◽  
Julia A. Segre ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Tumor Suppressor ◽  
B Cell ◽  
Cell Activation ◽  
Cell Transformation ◽  
Cell Lineage ◽  
Cell Types ◽  
B Cell Malignancies

Abstract Genes that are strongly repressed after B-cell activation are candidates for being inactivated, mutated, or repressed in B-cell malignancies. Krüppel-like factor 4 (Klf4), a gene down-regulated in activated murine B cells, is expressed at low levels in several types of human B-cell lineage lymphomas and leukemias. The human KLF4 gene has been identified as a tumor suppressor gene in colon and gastric cancer; in concordance with this, overexpression of KLF4 can suppress proliferation in several epithelial cell types. Here we investigate the effects of KLF4 on pro/pre–B-cell transformation by v-Abl and BCR-ABL, oncogenes that cause leukemia in mice and humans. We show that overexpression of KLF4 induces arrest and apoptosis in the G1 phase of the cell cycle. KLF4-mediated death, but not cell-cycle arrest, can be rescued by Bcl-XL overexpression. Transformed pro/pre-B cells expressing KLF4 display increased expression of p21CIP and decreased expression of c-Myc and cyclin D2. Tetracycline-inducible expression of KLF4 in B-cell progenitors of transgenic mice blocks transformation by BCR-ABL and depletes leukemic pre-B cells in vivo. Collectively, our work identifies KLF4 as a putative tumor suppressor in B-cell malignancies.

scholarly journals Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1008960
Author(s):  
Pilar Delgado ◽  
Ángel F. Álvarez-Prado ◽  
Ester Marina-Zárate ◽  
Isora V. Sernandez ◽  
Sonia M. Mur ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Transformation ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
Intratumoral Heterogeneity ◽  
Chromosome Translocations ◽  
Activation Induced Deaminase

Most B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GC B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their Ig genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG). AID promotes collateral damage in the form of chromosome translocations and off-target SHM, however, the exact contribution of AID activity to lymphoma generation and progression is not completely understood. Here we show using a conditional knock-in strategy that AID supra-activity alone is not sufficient to generate B cell transformation. In contrast, in the absence of UNG, AID supra-expression increases SHM and promotes lymphoma. Whole exome sequencing revealed that AID heavily contributes to lymphoma SHM, promoting subclonal variability and a wider range of oncogenic variants. Thus, our data provide direct evidence that UNG is a brake to AID-induced intratumoral heterogeneity and evolution of B cell lymphoma.

scholarly journals Cohesin Core Complex Gene Dosage Contributes to Germinal Center Derived Lymphoma Phenotypes and Outcomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Martin A. Rivas ◽  
Ceyda Durmaz ◽  
Andreas Kloetgen ◽  
Cristopher R. Chin ◽  
Zhengming Chen ◽  
...  
Keyword(s):  
B Cells ◽  
Tumor Suppressor ◽  
B Cell ◽  
Cell Fate ◽  
Plasma Cell ◽  
Germinal Center ◽  
Gene Dosage ◽  
B Cell Lymphoma ◽  
Dlbcl Patient ◽  
Atpase Subunit

The cohesin complex plays critical roles in genomic stability and gene expression through effects on 3D architecture. Cohesin core subunit genes are mutated across a wide cross-section of cancers, but not in germinal center (GC) derived lymphomas. In spite of this, haploinsufficiency of cohesin ATPase subunit Smc3 was shown to contribute to malignant transformation of GC B-cells in mice. Herein we explored potential mechanisms and clinical relevance of Smc3 deficiency in GC lymphomagenesis. Transcriptional profiling of Smc3 haploinsufficient murine lymphomas revealed downregulation of genes repressed by loss of epigenetic tumor suppressors Tet2 and Kmt2d. Profiling 3D chromosomal interactions in lymphomas revealed impaired enhancer-promoter interactions affecting genes like Tet2, which was aberrantly downregulated in Smc3 deficient lymphomas. Tet2 plays important roles in B-cell exit from the GC reaction, and single cell RNA-seq profiles and phenotypic trajectory analysis in Smc3 mutant mice revealed a specific defect in commitment to the final steps of plasma cell differentiation. Although Smc3 deficiency resulted in structural abnormalities in GC B-cells, there was no increase of somatic mutations or structural variants in Smc3 haploinsufficient lymphomas, suggesting that cohesin deficiency largely induces lymphomas through disruption of enhancer-promoter interactions of terminal differentiation and tumor suppressor genes. Strikingly, the presence of the Smc3 haploinsufficient GC B-cell transcriptional signature in human patients with GC-derived diffuse large B-cell lymphoma (DLBCL) was linked to inferior clinical outcome and low expression of cohesin core subunits. Reciprocally, reduced expression of cohesin subunits was an independent risk factor for worse survival int DLBCL patient cohorts. Collectively, the data suggest that Smc3 functions as a bona fide tumor suppressor for lymphomas through non-genetic mechanisms, and drives disease by disrupting the commitment of GC B-cells to the plasma cell fate.

scholarly journals Interplay between UNG and AID governs intratumoral heterogeneity in mature B cell lymphoma

2020 ◽  
Author(s):  
Pilar Delgado ◽  
Ángel F Álvarez-Prado ◽  
Ester Marina-Zárate ◽  
Isora V Sernandez ◽  
Sonia M Mur ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Transformation ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
B Cell Lymphoma ◽  
Intratumoral Heterogeneity ◽  
Chromosome Translocations ◽  
Activation Induced Deaminase

ABSTRACTMost B cell lymphomas originate from B cells that have germinal center (GC) experience and bear chromosome translocations and numerous point mutations. GCs B cells remodel their immunoglobulin (Ig) genes by somatic hypermutation (SHM) and class switch recombination (CSR) in their immunoglobulin (Ig) genes. Activation Induced Deaminase (AID) initiates CSR and SHM by generating U:G mismatches on Ig DNA that can then be processed by Uracyl-N-glycosylase (UNG). AID promotes collateral damage in the form of chromosome translocations and off-target SHM, however, the exact contribution of AID activity to lymphoma generation and progression is not completely understood. Here we show using a conditional knock-in strategy that AID supraactivity alone is not sufficient to generate B cell transformation. In contrast, in the absence of UNG, AID supra-expression increases SHM and promotes lymphoma. Whole exome sequencing revealed that AID heavily contributes to lymphoma SHM, promoting subclonal variability and a wider range of oncogenic variants. Thus, our data provide direct evidence that UNG is a brake to AID-induced intratumoral heterogeneity and evolution of B cell lymphoma.

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