Cancer arises from the perturbation of normal cells. This perturbation, most commonly, consists of the accumulation of genetic mutations in a single lineage of cells. We have recently provided formal proof of this sequential acquisition of mutations in normally-functioning hematopoietic stem and progenitor cells (HSPCs) in a subtype of acute myeloid leukemia (AML). While this was hypothesized for many years, it was not clear how many mutations a cell was able to acquire before losing its normal function and acquiring a leukemogenic phenotype. Our research has shown that HSPCs can harbor as many as 14 coding mutations while still retaining normal stem cell function. Moreover, these cells only differ from their fully-leukemic counterparts by 2-5 additional coding mutations. This indicates that, at least in a subset of leukemias, there are normally- functioning cells that are poised to become leukemogenic given the acquisition of a small number of additional mutations. These pre-leukemic cells are of particular interest as they are likely refractory to chemotherapy and could constitute a cellular reservoir capable of seeding a relapse. This study aims to characterize the response of pre-leukemic hematopoietic stem and progenitor cells (pHSPCs) to standard induction and consolidation chemotherapy as well as understand the contribution of pHSPCs to relapse in AML. Importantly, if long-term remission and eventual cure are to be attained, these cells may need to be therapeutically targeted to eliminate the potential for relapse. Additionally, the study of the pHSPCs will provide key insights into the earliest stages of leukemogenesis and identify the founder and progressor mutations involved in the evolution of AML.

Public Health Relevance

Acute myeloid leukemia (AML) is an aggressive clonal malignancy of the bone marrow caused by accumulation of multiple mutations in a single lineage of cells. This mutational acquisition can occur in normally-functioning stem cells that can persist after therapy and potentially acquire a small number of additional mutations, leading to the generation of relapsed disease. As relapse is the primary cause of death in AML patients, we must understand these cells and determine a mechanism by which they can be therapeutically targeted.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09A-L (20))
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Vallejo-Estrada, Yolanda
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Stanford University
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Corces, M Ryan; Buenrostro, Jason D; Wu, Beijing et al. (2016) Lineage-specific and single-cell chromatin accessibility charts human hematopoiesis and leukemia evolution. Nat Genet 48:1193-203
Corces-Zimmerman, M R; Majeti, R (2014) Pre-leukemic evolution of hematopoietic stem cells: the importance of early mutations in leukemogenesis. Leukemia 28:2276-82
Corces-Zimmerman, M Ryan; Hong, Wan-Jen; Weissman, Irving L et al. (2014) Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci U S A 111:2548-53