Functional significance of Pre-Leukemic HSC in Human Acute Myeloid Leukemia

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): 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.