Research ArticleLeukemia

Clonal Evolution of Preleukemic Hematopoietic Stem Cells Precedes Human Acute Myeloid Leukemia

Science Translational Medicine  29 Aug 2012:
Vol. 4, Issue 149, pp. 149ra118
DOI: 10.1126/scitranslmed.3004315

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Getting to the Root of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is an aggressive clonal malignancy of bone marrow progenitor cells caused by the accumulation of multiple mutations in a single lineage of cells. In the bone marrow, most cells are short-lived and the frequency of mutations is low, making it tough to explain how such a lineage of cells with multiple mutations could arise. In a new study, Jan et al. now propose a model in which AML develops by serial acquisition of mutations in long-lived self-renewing hematopoietic stem cells (HSCs). The authors directly tested their clonal evolution model by sequencing the exomes (the protein-coding regions of the genome) of AML cells and residual HSCs taken from patients with AML. First, they identified the coding mutations present in six AML patient samples by exome sequencing. Then, using cell surface markers to isolate rare residual HSCs by flow cytometry, the researchers discovered leukemia-associated mutations in the HSCs. Finally, the authors performed single-cell assays targeted to the identified mutations to determine the genotype of individual HSCs. They detected multiple cell clones in the HSC pool that contained some, but not all, of the mutations seen in the AML cells. Furthermore, the authors were able to determine the order of acquisition of the mutations that preceded development of AML. These results offer fresh insights into the early stages of AML and pinpoint preleukemic HSCs as an important therapeutic target to prevent relapse and to ensure durable clinical remission after chemotherapy.

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