The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation. © 2014 Nature America, Inc

Papaemmanuil, E., Rapado, I., Li, Y., Potter, N., Wedge, D., Tubio, J., et al. (2014). RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. NATURE GENETICS, 46(2), 116-125 [10.1038/ng.2874].

RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia

CAZZANIGA, GIOVANNI ITALO;BIONDI, ANDREA;
2014

Abstract

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation. © 2014 Nature America, Inc
Articolo in rivista - Articolo scientifico
Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Core Binding Factor Alpha 2 Subunit; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Gene Library; Gene Rearrangement; Genes, Tumor Suppressor; Homeodomain Proteins; Humans; Molecular Sequence Data; Oncogene Proteins, Fusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Recombination, Genetic; Sequence Analysis, DNA; Sequence Deletion; Transcription Factors; V(D)J Recombination; Genetic Variation; Genetics
English
2014
46
2
116
125
none
Papaemmanuil, E., Rapado, I., Li, Y., Potter, N., Wedge, D., Tubio, J., et al. (2014). RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. NATURE GENETICS, 46(2), 116-125 [10.1038/ng.2874].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/100843
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