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Cell. 2012 Jul 20;150(2):264-78. doi: 10.1016/j.cell.2012.06.023.

The origin and evolution of mutations in acute myeloid leukemia.

Author information

  • 1Department of Medicine, Washington University, St. Louis, MO 63110, USA.

Abstract

Most mutations in cancer genomes are thought to be acquired after the initiating event, which may cause genomic instability and drive clonal evolution. However, for acute myeloid leukemia (AML), normal karyotypes are common, and genomic instability is unusual. To better understand clonal evolution in AML, we sequenced the genomes of M3-AML samples with a known initiating event (PML-RARA) versus the genomes of normal karyotype M1-AML samples and the exomes of hematopoietic stem/progenitor cells (HSPCs) from healthy people. Collectively, the data suggest that most of the mutations found in AML genomes are actually random events that occurred in HSPCs before they acquired the initiating mutation; the mutational history of that cell is "captured" as the clone expands. In many cases, only one or two additional, cooperating mutations are needed to generate the malignant founding clone. Cells from the founding clone can acquire additional cooperating mutations, yielding subclones that can contribute to disease progression and/or relapse.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID:
22817890
[PubMed - indexed for MEDLINE]
PMCID:
PMC3407563
Free PMC Article

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