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

Lookup NU author(s): Dr Frederik van DelftORCiD

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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, similar to 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.


Publication metadata

Author(s): Papaemmanuil E, Rapado I, Li YL, Potter NE, Wedge DC, Tubio J, Alexandrov LB, Van Loo P, Cooke SL, Marshall J, Martincorena I, Hinton J, Gundem G, van Delft FW, Nik-Zainal S, Jones DR, Ramakrishna M, Titley I, Stebbings L, Leroy C, Menzies A, Gamble J, Robinson B, Mudie L, Raine K, O'Meara S, Teague JW, Butler AP, Cazzaniga G, Biondi A, Zuna J, Kempski H, Muschen M, Ford AM, Stratton MR, Greaves M, Campbell PJ

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2014

Volume: 46

Issue: 2

Pages: 116-125

Print publication date: 12/01/2014

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ng.2874

DOI: 10.1038/ng.2874


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Funding

Funder referenceFunder name
Research Foundation-Flanders (FWO)
077012/Z/05/ZWellcome Trust
11021Leukemia and Lymphoma Research
KKL407Kay Kendall Leukaemia Fund (KKLF)
MH-CR DRO 00064203University Hospital Motol
KKL417KKLF
WT088340MAWellcome Trust Senior Clinical Research Fellowship
WT100183MAWellcome Trust

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