Msh6 Protects Mature B Cells from Lymphoma by Preserving Genomic Stability

Peled, Jonathan U.; Sellers, Rani S.; Iglesias-Ussel, Maria D.; Shin, Dong Mi; Montagna, Cristina; Zhao, Chunfang; Li, Ziqiang; Edelmann, Winfried; Morse, Herbert C.; Scharff, Matthew D.

doi:10.2353/ajpath.2010.100234

Cited by 13 publications

(8 citation statements)

References 106 publications

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“…This could also explain partly the defect in maintenance of long-term Ab memory noted in Kap1-deleted mice, because MSH6 has been shown to be involved in the control of germinal center homeostasis and because SLAM molecules have been shown to be needed for long-term humoral reactions. 49,50 Finally, Kap1 deletion led to significant up-regulation of the serine protease inhibitor clade A3 (Serpina3) F-G genes and the glutathione S-transferase (Gstt) cluster. The functions of the products of these 2 gene clusters in the B-lymphoid lineage are undefined, and the results of our analyses warrant exploring further their role in B-cell development.…”

Section: Discussionmentioning

confidence: 99%

KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function

Sio¹,

Massacand

Barde³

et al. 2012

Blood

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Chromatin remodeling is fundamental for B-cell differentiation. In the present study, we explored the role of KAP1, the cofactor of KRAB-ZFP transcriptional repressors, in this process. B-lymphoidspecific Kap1-KO mice displayed reduced numbers of mature B cells, lower steadystate levels of Abs, and accelerated rates of decay of neutralizing Abs after viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an up-regulation of PTEN, the enzymatic counteractor of PIK3 signaling, and of genes encoding DNA-damage response factors, cell-cycle regulators, and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to several of these genes and controlled chromatin status at their promoters. Genome wide, KAP1 binding sites lacked active B cell-specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRABZFPs is enriched in B lymphocytes. Our results therefore reveal the role of KRAB/ KAP1-mediated epigenetic regulation in B-cell development and homeostasis. IntroductionEpigenetics play a major role in ontogeny and cell specification, as illustrated by human developmental diseases caused by mutations in components of the epigenetic machinery and by the phenotypic consequences of the knockout (KO) of epigenetic regulators on mouse embryogenesis and stem cell biology. 1 This level of regulation is also key to the lineage differentiation of adult tissues, in particular for the development of immune cells. As a corollary, altered epigenetic regulation has been linked to autoimmune and allergic diseases and to hematopoietic malignancies. 2 B-cell progenitors (Pro-B cells) derive from multipotent lymphoid progenitors in the bone marrow (BM). Pro-B cells initiate the IgH locus rearrangement, completed during maturation to B-precursor (Pre-B) cells. After rearrangement of an Ig light chain locus and surface expression of a complete IgM molecule, immature B cells egress from the BM and migrate to the spleen, where they undergo further maturation steps called transitional stages 1 and 2 (T1 and T2) and eventually differentiate into mature follicular (FO) and marginal zone (MZ) B cells. 3,4 FO cells are mostly composed of conventional B2 cells, which can recirculate and are responsible for T cell-dependent Ab production. In contrast, MZ B lymphocytes are sessile, nonconventional cells that, together with B1 cells, contribute to the T cell-independent Ab response. B1 cells predominantly reside in the peritoneal and pleural cavities and are thought to arise from a self-renewing fetal precursor located in the peritoneum or from B1 progenitors in adult BM. 4 B-cell development and homeostasis require the integration of external and internal clues. External stimuli are sensed mainly by the BCR and other membrane receptors (ie, IL-7R, Notch2, BAFFR, and various chemokine receptors). Signals from these receptors are the...

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Section: Discussionmentioning

confidence: 99%

KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function

Sio¹,

Massacand

Barde³

et al. 2012

Blood

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“…Thymic lymphomas were dissociated, filtered, and resuspended as described (50). To prepare metaphase spreads, cells were treated with colcemid for 3–6 hours, swelled, fixed, and dropped onto clean glass slides inside a humidity chamber.…”

Section: Methodsmentioning

confidence: 99%

The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair

et al. 2013

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Loss of the DNA mismatch repair protein MSH3 leads to the development of a variety of tumors in mice without significantly affecting survival rates, suggesting a modulating role for the MutSβ (MSH2-MSH3) complex in late onset tumorigenesis. To better study the role of MSH3 in tumor progression, we crossed Msh3−/− mice onto a tumor predisposing p53-deficient background. Survival of Msh3/p53 mice was not reduced compared to single p53 mutant mice; however, the tumor spectrum changed significantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis. Interestingly, Msh3−/− mouse embryonic fibroblasts displayed increased chromatid breaks and persistence of γH2AX foci following ionizing radiation, indicating a defect in DNA double strand break repair. Msh3/p53 tumors showed increased loss of heterozygosity, elevated genome-wide copy number variation, and a moderate microsatellite instability phenotype compared to Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal stability. Our results show that the MSH2-MSH3 complex is important for the suppression of late onset tumors due to its role in DNA double strand break repair as well as in DNA mismatch repair. Furthermore, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in p53-deficient tumorigenesis, and possibly plays a role in other chromosomally unstable tumors as well.

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“…Similar reasoning was suggested by Lucci-Cordisco et al when studying atypical MSH6 presentation with both commonly seen Lynch-related malignancies and leukemias. [45][46][47] This could also explain the low detection rate of clinical criteria, and the variability of Lynch syndrome phenotypes and tumor spectrums.…”

Section: Hematopoietic Malignanciesmentioning

confidence: 99%

Extracolonic Manifestations of Lynch Syndrome

Bansidhar

2012

Clinics in Colon and Rectal Surgery

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Lynch syndrome has classically been defined by several predominant malignancies. Initial clinical criteria for diagnosis of Lynch syndrome would miss 40% of affected individuals. As time has passed, our understanding of Lynch syndrome has evolved and will continue to do so. The number of cancer types that are included in the Lynch phenotype is growing. This has allowed clinicians to redefine Lynch syndrome, at risk populations, screening needs, and diagnostic criteria. Inclusion of extracolonic malignancies and alternative genetic pathways gives new insight into the true prevalence and penetrance of Lynch syndrome.

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Msh6 Protects Mature B Cells from Lymphoma by Preserving Genomic Stability

Cited by 13 publications

References 106 publications

KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function

KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function

The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair

Extracolonic Manifestations of Lynch Syndrome

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