CLONAL EVOLUTION OF HEMATOPOIETIC STEM CELLS DURING CHEMOTHERAPY AND TRANSPLANTATION

化疗和移植过程中造血干细胞的克隆进化

• 批准号: 9247764
• 负责人: Terrence Neal Wong
• 金额: $ 12.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247764
• 关键词: Academic Medical Centers; Adult; Aftercare; Aging-Related Process; Apoptosis; Autologous Stem Cell Transplantation; Autologous Transplantation; Biological Assay; Blood specimen; Bone Marrow; Cells; Chimera organism; Chromosome abnormality; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 7; Clinical; Clonal Evolution; Clonal Expansion; Clonal Hematopoietic Stem Cell; Clone Cells; Complex; Cytogenetics; Cytotoxic Chemotherapy; Data; Diagnosis; Diagnostic; Disease; Dysmyelopoietic Syndromes; Early Diagnosis; Elderly; Evolution; Exposure to; Fellowship; Five-Year Plans; Frequencies; Gene Expression; Gene Mutation; Genes; Goals; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Incidence; Individual; Lead; Leukocytes; Link; Lymphoma; Malignant - descriptor; Medicine; Mentors; Mentorship; Modeling; Monitor; Multiple Myeloma; Mutation; Myeloablative Chemotherapy; Patient Care; Patients; Physicians; Population; Publishing; RUNX1 gene; Radiation therapy; Recording of previous events; Refractory; Relapse; Research; Research Personnel; Resistance; Risk; Risk stratification; Role; Sampling; Scientist; Somatic Mutation; Stem cells; System; TP53 gene; Therapy-Related Acute Myeloid Leukemia; Time; Training; Training Programs; Transplantation; Universities; Washington; base; career; career development; cell type; chemotherapy; digital; experience; experimental study; fitness; high risk; in vivo; instructor; leukemogenesis; medical schools; mutant; next generation sequencing; normal aging; oncology; outcome forecast; peripheral blood; pressure; prevent; public health relevance; research and development; response; senescence; tool

 DESCRIPTION (provided by applicant): The applicant proposes a five year plan to provide the candidate with mentored research and career development training. He recently completed his formal training in the Hematology/Oncology fellowship (and Physician Scientist Training Program) at Washington University School of Medicine and was promoted to an Instructor of Medicine in the Division of Oncology. At this juncture of his career, he desires additional mentored support to facilitate his scientific and career goals. The ultimate goal of the candidate is to be an independent investigator in an academic medical center, studying normal and malignant hematopoiesis and taking care of patients with hematologic diseases and cancer. The experiments outlined in this application aim to understand the role of chemotherapy in promoting the competitive fitness advantage and subsequent expansion of certain chemo-resistant hematopoietic clones and its potential clinical ramifications. The proposed studies will be carried out at Washington University under the primary mentorship of Dr. Daniel Link. Dr. Link is a world- renowned leader in the field of hematopoiesis. He is also a highly experienced and well-regarded mentor who has successfully mentored numerous trainees to independence. Therapy-related acute myeloid leukemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy (Godley, et al; Semin Oncol 2008). The long-term goal of our research is to determine how exposure to cytotoxic therapy contributes to leukemogenesis. Hematopoietic stem and progenitor cells (HSPCs) accumulate somatic mutations during the normal aging process, resulting in a genetically heterogeneous HSPC population in healthy adult individuals (Welch, et al; Cell 2012). In our preliminary data, we used a sensitive error-corrected next-generation sequencing (NGS) approach to identify functional TP53 mutations in very small populations of peripheral blood leukocytes in healthy elderly individuals. Furthermore, in several cases of t-AML/t-MDS, we found that the driver TP53 mutation clonal at diagnosis was in fact present at low frequencies in the bone marrow prior to the initiation of chemotherapy. Based on these data, we hypothesize that cytotoxic therapy is providing a selective pressure resulting in a fitness advantage to HSPCs harboring certain somatic mutations, including those in TP53. To further expand upon this hypothesis, the following specific aims are proposed: 1) Determine the incidence and assess the clonal expansion of HSPCs harboring TP53 mutations in patients with relapsed/refractory lymphoma undergoing autologous stem cell transplantation, 2) Identify additional somatic mutations providing HSPCs with a competitive fitness advantage after cytotoxic chemotherapy and autologous transplantation, and 3) Characterize the mechanisms by which TP53 mutations confer competitive fitness to HSPCs after chemotherapy. These proposed experiments will define the degree to which intensive chemotherapy influences the clonal evolution of hematopoietic stem cells and define the mechanisms through which somatic mutations in TP53 (and related genes) provide certain HSPCs with a fitness advantage. Ultimately, we hope to develop diagnostic tools for the risk stratification and early detection of -AML/t-MDS and potentially prevent the evolution of this poor prognosis disease. In particular, a better understanding of the mechanisms by which functional TP53 mutations result in clonal HSPC expansion after chemotherapy may lead to strategies to potentially reduce the risk of t-AML/t-MDS.

 描述（由申请人提供）：申请人提出了一个五年计划，为候选人提供指导性研究和职业发展培训。他最近在华盛顿大学医学院完成了血液学/肿瘤学奖学金（和医师科学家培训计划）的正式培训。医学并晋升为肿瘤科医学讲师。在他职业生涯的这个阶段，他希望获得额外的指导支持，以促进他的科学和职业目标。候选人的最终目标是：成为学术医疗中心的独立研究者，研究正常和恶性造血并照顾患有血液疾病和癌症的患者。本申请中概述的实验旨在了解化疗在促进竞争性健康优势和随后扩大某些领域的作用。化疗抗性造血克隆及其潜在的临床影响将在华盛顿大学进行，他是造血领域世界知名的领导者。也是一位经验丰富、备受尊敬的导师，已成功指导众多学员独立治疗与治疗相关的急性髓性白血病（t-AML）和与治疗相关的骨髓增生异常综合征（t-MDS）是公认的细胞毒性化疗和化疗的并发症。 / 或放射治疗（Godley 等人；Semin Oncol 2008）我们研究的长期目标是确定细胞毒性治疗如何导致白血病发生。造血干细胞和祖细胞 (HSPC) 在正常衰老过程中积累体细胞突变，导致健康成年个体中出现遗传异质的 HSPC 群体（Welch 等人；Cell 2012）。下一代测序 (NGS) 方法可识别健康老年人外周血白细胞极小群体中的功能性 TP53 突变。 t-AML/t-MDS，我们发现诊断时的驱动 TP53 突变克隆实际上在开始化疗之前以较低的频率存在于骨髓中。根据这些数据，我们发现细胞毒性疗法提供了选择性。压力导致含有某些体细胞突变（包括 TP53 突变）的 HSPC 具有适应性优势。为了进一步扩展这一假设，提出以下具体目标：1）确定 HSPC 的发生率并评估克隆扩增。在接受自体干细胞移植的复发/难治性淋巴瘤患者中携带 TP53 突变，2) 识别其他体细胞突变，为 HSPC 在细胞毒性化疗和自体移植后提供竞争性适应性优势，以及 3) 表征 TP53 突变赋予竞争性适应性的机制这些拟议的实验将确定化疗后的 HSPC 影响造血干细胞克隆进化的程度，并确定体细胞突变的机制。最终，我们希望开发出用于 AML/t-MDS 风险分层和早期检测的诊断工具，并有可能预防这种不良预后疾病的发展。更好地了解功能性 TP53 突变导致化疗后克隆 HSPC 扩增的机制可能会导致制定潜在降低 t-AML/t-MDS 风险的策略。