Journal article
Clonal Architecture of Secondary Acute Myeloid Leukemia
The New England journal of medicine, Vol.366(12), pp.1090-1098
03/22/2012
DOI: 10.1056/NEJMoa1106968
PMCID: PMC3320218
PMID: 22417201
Abstract
BACKGROUND
The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood.
METHODS
We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations.
RESULTS
Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene.
CONCLUSIONS
Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.)
Details
- Title: Subtitle
- Clonal Architecture of Secondary Acute Myeloid Leukemia
- Creators
- Matthew J. Walter - Washington University in St. LouisDong Shen - Washington University in St. LouisLi Ding - Washington University in St. LouisJin Shao - Washington University in St. LouisDaniel C. Koboldt - Washington University in St. LouisKen Chen - Bioinformatics & Computational BiologyDavid E. Larson - Washington University in St. LouisMichael D. McLellan - Washington University in St. LouisDavid Dooling - Washington University in St. LouisRachel Abbott - Washington University in St. LouisRobert Fulton - Washington University in St. LouisVincent Magrini - Washington University in St. LouisHeather Schmidt - Washington University in St. LouisJoelle Kalicki-Veizer - Washington University in St. LouisMichelle O'Laughlin - Washington University in St. LouisXian Fan - Washington University in St. LouisMarcus Grillot - Washington University in St. LouisSarah Witowski - Washington University in St. LouisSharon Heath - Washington University in St. LouisJohn L. Frater - Washington University in St. LouisWilliam Eades - Washington University in St. LouisMichael Tomasson - Washington University in St. LouisPeter Westervelt - Washington University in St. LouisJohn F. DiPersio - Washington University in St. LouisDaniel C. Link - Washington University in St. LouisElaine R. Mardis - Washington University in St. LouisTimothy J. Ley - Washington University in St. LouisRichard K. Wilson - Washington University in St. LouisTimothy A. Graubert - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- The New England journal of medicine, Vol.366(12), pp.1090-1098
- Publisher
- Massachusetts Medical Soc
- DOI
- 10.1056/NEJMoa1106968
- PMID
- 22417201
- PMCID
- PMC3320218
- ISSN
- 0028-4793
- eISSN
- 1533-4406
- Number of pages
- 9
- Grant note
- UL1RR024992 / National Center for Research Resources; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) RC2HL102927 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Howard Hughes Medical Institute R01HL082973; RC2HL102927; U54HG003079; P01CA101937 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P01CA101937 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U54HG003079 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI)
- Language
- English
- Date published
- 03/22/2012
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Health and Human Physiology; Internal Medicine
- Record Identifier
- 9984359695802771
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