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

Joy Bianchi (1, 2) , Valentine Murigneux (1) , Marie Bedora-Faure (1) , Chloé Lescale (1) , Ludovic Deriano (1)

1 Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer
2 Cellule Pasteur

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.

Keywords: cancer genome landscape; structural variation; breakage-fusion-bridge; T cell lymphoma; T cell development; DNA damage; RAG1/2 nuclease

Domains: Life Sciences [q-bio]; Cancer; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Molecular biology; Life Sciences [q-bio]; Cellular Biology; Life Sciences [q-bio]; Biochemistry, Molecular Biology; Genomics [q-bio.GN]; Life Sciences [q-bio]; Genetics

Joy Bianchi, Valentine Murigneux, Marie Bedora-Faure, Chloé Lescale, Ludovic Deriano. Breakage-Fusion-Bridge Events Trigger Complex Genome Rearrangements and Amplifications in Developmentally Arrested T Cell Lymphomas. Cell Reports, 2019, 27 (10), pp.2847-2858.e4. ⟨10.1016/j.celrep.2019.05.014⟩. ⟨pasteur-02757480⟩