Breakage-Fusion-Bridge Events Trigger Complex Genome Rearrangements and Amplifications in Developmentally Arrested T Cell Lymphomas

Abstract

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. : Using p53-deficient T cell lymphoma mouse models, Bianchi et al. show that breakage-fusion-bridge events trigger complex focal genome rearrangements and amplifications in developmentally arrested lymphoblastic cells, leading to unique genome and transcriptome signatures found in some human hematological cancers. Keywords: cancer genome landscape, T cell development, T cell lymphoma, DNA damage, structural variation, breakage-fusion-bridge, RAG1/2 nuclease