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Gene expression analysis of B cell lymphomas from representative IµHABcl6, IµHABcl6 Ung-/- Msh2-/-, and IµHABcl6 Msh2-/- mouse models.

ABSTRACT: Somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes are genomic modification events that 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 (U-G) mismatches are subsequently processed by low-fidelity base-excision (BER) and mismatch repair (MMR) pathways to yield mutations and DNA strand lesions. Although off-target AID activity also contributes to oncogenic point mutations and chromosome translocations associated with B cell lymphomas, the role of downstream AID-associated DNA repair pathways in the pathogenesis of these lymphomas is unknown. Here, we show that simultaneous BER and MMR deficiency causes genomic instability and a shorter latency to the development of a BCL6-driven GC B cell lymphoma. In contrast, loss of BER alone is highly protective against B cell transformation while loss of MMR fosters the development of a variety of malignancies. These findings lend insight into a complex interplay between AID-associated BER and MMR pathways that produces a net protective effect against GC B cell lymphomagenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE48304 | GEO | 2015/12/08

SECONDARY ACCESSION(S): PRJNA209628

REPOSITORIES: GEO

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Gene expression analysis of B cell lymphomas from representative IÂµHABcl6, IÂµHABcl6 Ung-/- Msh2-/-, and IÂµHABcl6 Msh2-/- mouse models.

Project description:Somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin (Ig) genes are genomic modification events that 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 (U-G) mismatches are subsequently processed by low-fidelity base-excision (BER) and mismatch repair (MMR) pathways to yield mutations and DNA strand lesions. Although off-target AID activity also contributes to oncogenic point mutations and chromosome translocations associated with B cell lymphomas, the role of downstream AID-associated DNA repair pathways in the pathogenesis of these lymphomas is unknown. Here, we show that simultaneous BER and MMR deficiency causes genomic instability and a shorter latency to the development of a BCL6-driven GC B cell lymphoma. In contrast, loss of BER alone is highly protective against B cell transformation while loss of MMR fosters the development of a variety of malignancies. These findings lend insight into a complex interplay between AID-associated BER and MMR pathways that produces a net protective effect against GC B cell lymphomagenesis. Representative B cell lymphomas from 3 IÂµHABcl6, 6 IÂµHABcl6 Ung-/- Msh2-/-, and 5 IÂµHABcl6 Msh2-/- mice were analyzed in this study. Total RNA was extracted from frozen tumor cells and processed according to Illumina standard protocols.

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