Breakage-fusion-bridge events trigger complex genome rearrangements and amplifications in developmentally arrested T cell lymphomas

Summary To 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.