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.

• MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genetická variace * MeSH
• genová knihovna MeSH
• genová přestavba genetika   MeSH
• homeodoménové proteiny genetika   MeSH
• lidé MeSH
• molekulární sekvence - údaje MeSH
• pre-B-buněčná leukemie genetika   MeSH
• protein PEBP2A2 genetika   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• rekombinace genetická genetika   MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• sekvenční delece genetika   MeSH
• transkripční faktory bHLH genetika   MeSH
• transkripční faktory genetika   MeSH
• tumor supresorové geny MeSH
• V(D)J rekombinace genetika   MeSH
• variabilita počtu kopií segmentů DNA genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

B-cell precursor childhood acute lymphoblastic leukemia with ETV6-RUNX1 (TEL-AML1) fusion has an overall good prognosis, but relapses occur, usually after cessation of treatment and occasionally many years later. We have investigated the clonal origins of relapse by comparing the profiles of genomewide copy number alterations at presentation in 21 patients with those in matched relapse (12-119 months). We identified, in total, 159 copy number alterations at presentation and 231 at relapse (excluding Ig/TCR). Deletions of CDKN2A/B or CCNC (6q16.2-3) or both increased from 38% at presentation to 76% in relapse, suggesting that cell-cycle deregulation contributed to emergence of relapse. A novel observation was recurrent gain of chromosome 16 (2 patients at presentation, 4 at relapse) and deletion of plasmocytoma variant translocation 1 in 3 patients. The data indicate that, irrespective of time to relapse, the relapse clone was derived from either a major or minor clone at presentation. Backtracking analysis by FISH identified a minor subclone at diagnosis whose genotype matched that observed in relapse ∼ 10 years later. These data indicate subclonal diversity at diagnosis, providing a variable basis for intraclonal origins of relapse and extended periods (years) of dormancy, possibly by quiescence, for stem cells in ETV6-RUNX1(+) acute lymphoblastic leukemia.

• MeSH
• akutní lymfatická leukemie genetika   metabolismus   mortalita   terapie   MeSH
• cyklin C MeSH
• dítě MeSH
• fúzní onkogenní proteiny genetika   metabolismus   MeSH
• inhibitor p15 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• inhibitor p16 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• lidé MeSH
• lidské chromozomy, pár 16 genetika   metabolismus   MeSH
• lidské chromozomy, pár 6 genetika   metabolismus   MeSH
• předškolní dítě MeSH
• protein PEBP2A2 MeSH
• recidiva MeSH
• sekvenční delece * MeSH
• translokace genetická * MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH