Abstract
SummaryTo reveal the relative contribution of the recombination activating gene (RAG)1/2 nuclease to lymphomagenesis, we conducted a genome-wide analysis of T cell lymphomas from p53-deficient mice expressing or lacking RAG2. We found that while p53−/− lymphoblastic T cells harbor primarily ectopic DNA deletions, Rag2−/−p53−/− T cell lymphomas display complex genomic rearrangements associated with amplification of the chromosomal location 9qA4-5.3. We show that this amplicon is generated by breakage-fusion-bridge during mitosis and arises distinctly in T cell lymphomas originating from an early progenitor stage. Notably, we report amplification of the corresponding syntenic region (11q23) in a subset of human leukemia leading to the overexpression of several cancer genes, including MLL/KMT2A. Our findings provide direct evidence that lymphocytes undergo malignant transformation through distinct genome architectural routes that are determined by both RAG-dependent and RAG-independent DNA damage and a block in cell development.
Highlights
Genetic mutations are thought to result from the combination of specific DNA damage and DNA repair processes that modify the DNA sequence and clonal selection mechanisms that contribute to cancer evolution (Jackson and Bartek, 2009; Stratton et al, 2009; Yates and Campbell, 2012)
T Cell Lymphomagenesis in Rag2À/À p53À/À and p53À/À Mice To decipher the role of the V(D)J recombinase in lymphomagenesis, we bred Rag2À/À mice (Shinkai et al, 1992) with p53À/À mice (Jacks et al, 1994) and followed tumor appearance in p53À/À and Rag2À/À p53À/À mice (Figures S1 and S2)
We analyzed T cell lymphomas originating from these mice at the DNA level by performing whole genome deep sequencing of four p53À/À and four Rag2À/Àp53À/À thymic T cell tumors at an average coverage of 36X (Figure S2; Table S1)
Summary
Genetic mutations are thought to result from the combination of specific DNA damage and DNA repair processes that modify the DNA sequence and clonal selection mechanisms that contribute to cancer evolution (Jackson and Bartek, 2009; Stratton et al, 2009; Yates and Campbell, 2012). Immature lymphoid cells are exposed to potentially harmful DNA damage events as DNA double-strand breaks (DSBs) are generated during the assembly of immunoglobulin (Ig) and T cell receptor (TCR) variable region exons via a cut-and-paste mechanism termed V(D)J (variable [diversity] joining) recombination (Bassing et al, 2002). This process is initiated when the recombination activating gene products RAG1 and RAG2, forming the RAG endonuclease, introduce DSBs between V, D, or J coding gene segments and flanking recombination signal sequences (RSSs). In addition to promoting adaptive immunity, RAGs have been implicated in the genesis of genetic instability associated with lymphoid malignancy (Marculescu et al, 2006; Onozawa and Aplan, 2012; Roth, 2014)
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