Clonal Evolution of Pre-Leukemic HSC Precedes Human AML

Acute myeloid leukemia is an aggressive clonal malignancy of the bone marrow that is the direct result of sequential acquisition of mutations in a single lineage of cells. In this study, we investigate a model in which this mutational acquisition occurs serially in long-lived self-renewing hematopoietic stem cells eventually resulting in frank acute myeloid leukemia. Coding mutations in multiple AML patients were identified using exome sequencing followed by sanger sequencing validation. The level of these mutations was then assessed in residual hematopoietic stem cells from each patient using targeted deep sequencing. These population-level estimates of mutant allele burden were then validated in single cell assays targeted to the identified mutations. This allowed for determination of the order of acquisition of the mutations that preceded the development of the leukemia. The results of this study identify pre-leukemic hematopoietic stem cell clones that could contribute to patient relapse and outcome.]]>
Samples were included in this cohort study based on our ability to prospectively isolate hematopoietic stem cells from the diagnosis leukemia samples by differential cell surface marker expression.]]>
This study was carried out using samples collected between 2006 and 2011. The research was preformed between January 2010 and April 2012.]]>