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

E. Papaemmanuil, I. Rapado, Y. Li, NE. Potter, DC. Wedge, J. Tubio, LB. Alexandrov, P. Van Loo, SL. Cooke, J. Marshall, I. Martincorena, J. Hinton, G. Gundem, FW. van Delft, S. Nik-Zainal, DR. Jones, M. Ramakrishna, I. Titley, L. Stebbings, C....

Nature genetics. 2014 ; 46 (2) : 116-25.

Nat Genet
ISSN 1546-1718
Medvik
Zdroj

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz https://www.medvik.cz/link/bmc14050702

Online Plný text

NLK ProQuest Central od 2000-01-01 do Před 1 rokem
Medline Complete (EBSCOhost) od 1998-06-01 do 2015-11-30
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 2000-01-01 do Před 1 rokem

PubMed 24413735
DOI 10.1038/ng.2874
Knihovny.cz E-zdroje

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.

Citace poskytuje Crossref.org

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

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