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

描述(由申请人提供)： 癌症是由正常细胞的扰动引起的。这种扰动，最常见的是，在单一细胞谱系中基因突变的积累。我们最近提供了在急性髓系白血病(AML)的一个亚型中连续获得正常功能的造血干细胞和祖细胞(HSPC)突变的正式证据。虽然这是多年来的假设，但目前还不清楚一个细胞在失去正常功能并获得白血病表型之前能够获得多少突变。我们的研究表明，HSPC可以包含多达14个编码突变，同时仍然保持正常的干细胞功能。此外，这些细胞只与完全白血病的对应细胞不同。 通过2-5个额外的编码突变。这表明，至少在白血病的一个子集中，存在功能正常的细胞，由于获得了少量额外的突变，这些细胞有可能成为白血病细胞。这些“白血病前期”细胞特别令人感兴趣，因为它们很可能对化疗无效，并可能构成一个能够导致复发的细胞储存库。本研究旨在研究白血病前造血干细胞和造血祖细胞对标准诱导巩固化疗的反应，并了解其在急性髓系白血病复发中的作用。重要的是，如果要实现长期缓解和最终治愈，可能需要针对这些细胞进行治疗，以消除复发的可能性。此外，对PHSPC的研究将提供 对白血病发生的早期阶段的关键洞察，并确定急性髓细胞白血病进化中涉及的创始人和进展者突变。

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.