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.

Original publication

DOI

10.1038/ng.2874

Type

Journal article

Journal

Nat Genet

Publication Date

02/2014

Volume

46

Pages

116 - 125

Keywords

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, Genetic Variation, 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