Clonal origins of relapse in ETV6-RUNX1 acute lymphoblastic leukemia
- 9 June 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 117 (23), 6247-6254
- https://doi.org/10.1182/blood-2010-10-314674
Abstract
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.Keywords
This publication has 48 references indexed in Scilit:
- The correlation pattern of acquired copy number changes in 164 ETV6/RUNX1-positive childhood acute lymphoblastic leukemiasHuman Molecular Genetics, 2010
- Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant AstrocytomasCancer Research, 2010
- Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic LeukemiaScience, 2008
- Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemiaBlood, 2008
- The Identification of MicroRNAs in a Genomically Unstable Region of Human Chromosome 8q24Molecular Cancer Research, 2008
- Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarrayBlood, 2008
- Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subcloneBlood, 2007
- TEL-AML1 transgenic zebrafish model of precursor B cell acute lymphoblastic leukemiaProceedings of the National Academy of Sciences of the United States of America, 2006
- Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)Blood, 2006
- Drug resistance in cancer: Principles of emergence and preventionProceedings of the National Academy of Sciences of the United States of America, 2005