A Lack of DNA Mismatch Repair on an Athymic Murine Background Predisposes to Hematologic Malignancy

“…UNG-deficient mice have been shown to develop an FL, whereas MSH2-deficient mice develop numerous malignancies but predominantly pre-B-cell and T-cell lymphomas. 37,38,42,43 As a central component of MMR, MSH2 provides global protection against genomic instability. 44,45 Indeed, among 18 Ung 2/2 Msh2 2/2 control mice, median survival was 7 months with 3 pre-B-cell lymphomas and 5 T-cell lymphomas but no mature B-cell lymphomas ( Figure 2).…”

Section: Msh2mentioning

confidence: 99%

AID-associated DNA repair pathways regulate malignant transformation in a murine model of BCL6-driven diffuse large B-cell lymphoma

Booth²,

Liu

et al. 2016

Blood

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• The combined effects of AIDassociated base excision and MMR delay the development of BCL6-driven DLBCL.• UNG single deficiency prevents the development of BCL6-driven DLBCL.Somatic hypermutation and class-switch recombination of the immunoglobulin (Ig) genes occur in germinal center (GC) B cells and are initiated through deamination of cytidine to uracil by activation-induced cytidine deaminase (AID). Resulting uracil-guanine mismatches are processed by uracil DNA glycosylase (UNG)-mediated base-excision repair and MSH2-mediated mismatch repair (MMR) to yield mutations and DNA strand lesions.Although off-target AID activity also contributes to oncogenic point mutations and chromosome translocations associated with GC and post-GC B-cell lymphomas, the role of downstream AID-associated DNA repair pathways in the pathogenesis of lymphoma is unknown. Here, we show that simultaneous deficiency of UNG and MSH2 or MSH2 alone causes genomic instability and a shorter latency to the development of BCL6-driven diffuse large B-cell lymphoma (DLBCL) in a murine model. The additional development of several BCL6-independent malignancies in these mice underscores the critical role of MMR in maintaining general genomic stability. In contrast, absence of UNG alone is highly protective and prevents the development of BCL6-driven DLBCL. We further demonstrate that clonal and nonclonal mutations arise within non-Ig AID target genes in the combined absence of UNG and MSH2 and that DNA strand lesions arise in an UNG-dependent manner but are offset by MSH2. These findings lend insight into a complex interplay whereby potentially deleterious UNG activity and general genomic instability are opposed by the protective influence of MSH2, producing a net protective effect that promotes immune diversification while simultaneously attenuating malignant transformation of GC B cells. (Blood. 2016;127(1):102-112) Introduction Acquired somatic mutations and chromosome translocations are a hallmark of cancer that arise as a pathological result of a DNA repair response to a genotoxic event.1 In contrast, the introduction of nontemplated nucleotides and DNA double-strand breaks (DSBs) is part of the normal developmental program in germinal center (GC) B cells. Somatic hypermutation (SHM) and class-switch recombination (CSR) of the immunoglobulin (Ig) genes promotes antibody diversification in GC B cells, but the nature of these genetic remodeling events makes these cells uniquely vulnerable to malignant transformation.2 Numerous types of B-cell malignancies arise from GC and post-GC B cells including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, follicular lymphoma (FL), lymphoplasmacytic lymphoma, multiple myeloma, and Hodgkin lymphoma. 3 SHM and CSR are both initiated by activation-induced cytidine deaminase (AID), 4 a GC B-cell enzyme that lacks strict target specificity and is also able to introduce mutations and DSBs into non-Ig genes throughout the genome.5-12 A role for AID in lymphomagenesis is supported by the presence of cha...

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“…For example, in FA patients, MSH2 loss could signify that bone marrow failure is improbable but that leukemia is developing. Indeed, MMR-deficient mice are predisposed to hematologic malignancy 67,68 and MMR loss is implicated in acute myeloid leukemia in humans. [69][70][71] Not only does loss of MMR protein expression and function contribute to cancer susceptibility, it also contributes to chemoresistance.…”

Section: Modulators Of Fa Cell Fitness and Clinical Potentialmentioning

confidence: 99%

What is wrong with Fanconi anemia cells?

Cantor¹,

Brosh

2014

Cell Cycle

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A Lack of DNA Mismatch Repair on an Athymic Murine Background Predisposes to Hematologic Malignancy

Cited by 17 publications

References 41 publications

Role of MUTYH and MSH2 in the Control of Oxidative DNA Damage, Genetic Instability, and Tumorigenesis

Role of MUTYH and MSH2 in the Control of Oxidative DNA Damage, Genetic Instability, and Tumorigenesis

AID-associated DNA repair pathways regulate malignant transformation in a murine model of BCL6-driven diffuse large B-cell lymphoma

What is wrong with Fanconi anemia cells?

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