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

• 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
• 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

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）： 癌症是由正常细胞的扰动引起的。这种扰动最常见的是由单个细胞谱系中基因突变的积累组成。我们最近提供了正式证据，证明在急性髓系白血病 (AML) 亚型中功能正常的造血干细胞和祖细胞 (HSPC) 中连续获得突变。尽管这一假设已存在多年，但尚不清楚细胞在失去正常功能并获得致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，同时仍保留正常的干细胞功能。此外，这些细胞仅与完全白血病细胞不同 通过 2-5 个额外的编码突变。这表明，至少在白血病的一个亚型中，存在功能正常的细胞，在获得少量额外突变后将成为白血病细胞。这些“白血病前”细胞特别令人感兴趣，因为它们可能对化疗耐药，并且可能构成能够播种复发的细胞库。本研究旨在表征白血病前期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 复发的影响。重要的是，如果要实现长期缓解和最终治愈，可能需要对这些细胞进行治疗以消除复发的可能性。此外，pHSPC 的研究将提供 对白血病发生最早阶段的关键见解，并确定参与 AML 进化的始祖和进展突变。