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

白血病前期 HSC 在人类急性髓系白血病中的功能意义

基本信息

批准号：
8595776
负责人：
Michael Ryan Corces
金额：
$ 4.22万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8595776
关键词：
Acute Myelocytic Leukemia Address Affect Biological Assay Blood Blood Cells Bone Marrow Cause of Death Cell Lineage Cell physiology Cells Clinical Clonal Evolution Code DNA Development Diagnosis Diagnostic Disease Disease Progression Disease remission Event Evolution FLT3 gene Frequencies Gene Mutation Generations Genomics Hematopoiesis Hematopoietic Hematopoietic stem cells Human Lead Lentivirus Leukemic Cell Leukemic Hematopoietic Stem Cell Life Malignant Neoplasms Marrow Mediating Modeling Mutation NPM1 gene Nature Normal Cell Outcome Patients Pattern Phenotype Prevalence Process Production Recurrent disease Refractory Relapse Research Resistance SNP genotyping Sampling Staging Stereotyping System Testing Xenograft procedure adult stem cell cell type chemotherapy deep sequencing exome sequencing gain of function mutation insight interest leukemia leukemogenesis loss of function mutation overexpression public health relevance reconstitution response self-renewal small hairpin RNA stem stem cells therapeutic target

Acute Myelocytic Leukemia Address Affect Biological Assay Blood Blood Cells Bone Marrow Cause of Death Cell Lineage Cell physiology Cells Clinical Clonal Evolution Code DNA Development Diagnosis Diagnostic Disease Disease Progression Disease remission Event Evolution FLT3 gene Frequencies Gene Mutation Generations Genomics Hematopoiesis Hematopoietic Hematopoietic stem cells Human Lead Lentivirus Leukemic Cell Leukemic Hematopoietic Stem Cell Life Malignant Neoplasms Marrow Mediating Modeling Mutation NPM1 gene Nature Normal Cell Outcome Patients Pattern Phenotype Prevalence Process Production Recurrent disease Refractory Relapse Research Resistance SNP genotyping Sampling Staging Stereotyping System Testing Xenograft procedure adult stem cell cell type chemotherapy deep sequencing exome sequencing gain of function mutation insight interest leukemia leukemogenesis loss of function mutation overexpression public health relevance reconstitution response self-renewal small hairpin RNA stem stem cells therapeutic target

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项目摘要

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.

描述（由申请人提供）：癌症来自正常细胞的扰动。这种扰动最常见的是由单个细胞谱系中的遗传突变积累。最近，我们提供了正常功能造血干细胞和祖细胞（HSPC）的突变的正式证明。尽管这是多年来的假设，但尚不清楚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可以携带多达14个编码突变，同时仍保持正常的干细胞功能。此外，这些细胞仅与它们的全白血病差异通过2-5个其他编码突变。这表明，至少在白血病的一部分中，鉴于获得了少数其他突变，通常会有一些功能性的细胞成为白血病。这些“清真血症前”细胞特别有意义，因为它们可能对化学疗法难治性，并且可能构成能够播种复发的细胞储层。这项研究旨在表征白血病前造血干细胞和祖细胞（PHSPC）对标准诱导和巩固化疗的反应，并了解PHSPC对AML复发的贡献。重要的是，如果要实现长期缓解和最终治愈，则可能需要将这些细胞靶向以消除复发的潜力。此外，对PHSPC的研究将提供对白血病的最早阶段的主要见解，并确定与AML进化有关的创始人和进步者突变。