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: 9904913
• 负责人: Terrence Neal Wong
• 金额: $ 12.14万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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/9904913
• 关键词: AML/MDS; Academic Medical Centers; Adult; Aftercare; 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; 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; Peripheral Stem Cell Transplantation; Physicians; Population; Process; Publishing; RUNX1 gene; Radiation therapy; Recording of previous events; Refractory; Relapse; Research; Research Personnel; Resistance; Risk; Risk stratification; Role; Sampling; Scientist; Somatic Mutation; 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; leukemic transformation; 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，并晋升为肿瘤学系的医学讲师。在他职业生涯的这个关键时刻，他希望得到更多的指导支持，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，并照顾血液病和癌症患者。本申请中概述的实验旨在了解化学疗法在促进某些化学抗性造血克隆的竞争适应性优势和随后的扩增中的作用及其潜在的临床后果。拟议的研究将在华盛顿大学进行，主要由丹尼尔林克博士指导。林博士是世界著名的造血领域的领导者.他也是一位经验丰富、备受推崇的导师，成功地指导了许多学员走向独立。治疗相关急性髓性白血病（t-AML）和治疗相关骨髓增生异常综合征（t-MDS）是细胞毒性化疗和/或放疗的公认并发症（Godley等人; Semin Oncol 2008）。我们研究的长期目标是确定暴露于细胞毒性治疗如何促进白血病发生。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的遗传异质性HSPC群体（Welch等人; Cell 2012）。在我们的初步数据中，我们使用了一种灵敏的纠错下一代测序（NGS）方法来识别健康老年人外周血白细胞中非常小的人群中的功能性TP 53突变。此外，在一些t-AML/t-MDS病例中，我们发现诊断时的驱动TP 53突变克隆实际上在化疗开始前以低频率存在于骨髓中。基于这些数据，我们假设细胞毒性治疗提供了一种选择性压力，导致携带某些体细胞突变（包括TP 53中的体细胞突变）的HSPC具有适应性优势。为了进一步扩展这一假设，提出了以下具体目标：1）在经历自体干细胞移植的复发性/难治性淋巴瘤患者中确定携带TP 53突变的HSPC的发生率并评估其克隆扩增，2）鉴定在细胞毒性化疗和自体移植后为HSPC提供竞争适应性优势的额外体细胞突变，以及3）表征TP 53突变在化疗后赋予HSPC竞争性适应性的机制。这些拟议的实验将定义强化化疗影响造血干细胞克隆进化的程度，并定义TP 53（和相关基因）中的体细胞突变为某些HSPC提供适应性优势的机制。最终，我们希望开发用于风险分层和早期检测-AML/t-MDS的诊断工具，并可能预防这种预后不良疾病的演变。特别是，更好地了解功能性TP 53突变导致化疗后克隆HSPC扩增的机制可能会导致潜在降低t-AML/t-MDS风险的策略。