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（由适用提供）：适用的提案为五年计划提供了有关研究和职业发展培训的候选人。他最近在华盛顿大学医学院完成了血液学/肿瘤学奖学金（以及医师科学家培训计划）的正式培训，并被晋升为肿瘤学系的医学教练。在他职业生涯的这个关头，他希望提供更多的指导支持，以支持他的科学和职业目标。候选人的最终目标是成为学术医学中心的独立研究员，研究正常和恶性造血症并照顾血液学疾病和癌症患者。该应用程序中概述的实验旨在了解化学疗法在促进竞争性健身优势和随后扩展某些化学抗性造血克隆及其潜在的临床后果方面的作用。拟议的研究将在华盛顿大学以丹尼尔·林克（Daniel Link）博士的主要心态进行。 Link博士是造血领域的世界知名领导者。他还是一个经验丰富且备受推崇的心态，他成功地介绍了众多学员的独立性。与治疗相关的急性髓样白血病（T-AML）和与治疗相关的骨髓增生性综合征（T-MDS）是细胞毒性化学疗法和/或放射疗法的良好识别并发症（Godley等人； Semin Oncol 2008）。我们研究的长期目标是确定接触细胞毒性疗法的暴露是如何促进白血病发生的。造血干细胞和祖细胞（HSPC）在正常衰老过程中积累了体细胞突变，导致健康成年个体的遗传异质HSPC种群（Welch等人； Cell; Cell; Cell 2012）。在我们的初步数据中，我们使用了敏感的错误校正下一代测序（NGS）方法来鉴定在健康老年人中非常小的外周血白细胞种群中的功能性TP53突变。此外，在某些T-AML/T-MD的情况下，我们发现诊断时的驱动器TP53突变克隆实际上是在化学疗法倡议之前以低频率出现的。基于这些数据，我们假设细胞毒性疗法正在提供选择性的压力，从而为具有某些体细胞突变（包括TP53中的hSPC）带来了适应性优势。为了进一步扩展这一假设，提出了以下具体目的：1）确定与携带/耐火性淋巴病的患者的HSPC的异位膨胀和评估，该HSPC的克隆扩展具有TP53突变/耐火性淋巴瘤，并在自体内干细胞移植中，2）鉴定出具有竞争能力的HSPC，并确定具有竞争力氧化的其他体细胞，并识别出具有竞争力的功能，并具有竞争力的功能，并具有竞争力的功能。 TP53突变会在化学疗法后与HSPC竞争适应性的机制。这些提出的实验将定义强化化学疗法影响造血干细胞的克隆演化的程度，并定义了TP53（及相关基因）中的体细胞突变提供具有适应性优势的某些HSPC的机制。最终，我们希望开发诊断工具，以进行风险分层和早期检测-AML/T -MD，并有可能阻止这种不良预后疾病的演变。特别是，更好地理解功能性TP53突变导致化学疗法后克隆HSPC扩展的机制可能会导致策略有可能降低T-AML/T-MD的风险。