The Impact of Donor Hematopoietic DNMT3A Mutations in Stem Cell Transplant Recipients

供体造血 DNMT3A 突变对干细胞移植受者的影响

• 批准号: 10284166
• 负责人: Christopher James Gibson
• 金额: $ 21.99万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10284166
• 关键词: Acute Myelocytic Leukemia; Advisory Committees; Affect; Allogenic; Area; Biologic Characteristic; Biological Assay; Biological Process; Biology; Biometry; Bone Marrow; Cardiovascular Diseases; Caring; Cells; Characteristics; Clinical; Clonal Evolution; Clonal Expansion; Collaborations; Communities; Cyclophosphamide; Dana-Farber Cancer Institute; Data; Data Science; Development Plans; Disease; Disease remission; Donor Selection; Donor person; Engraftment; Environment; Genes; Genomics; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histologic; Immune; Immune Evasion; Immune system; Immunologic Surveillance; Immunologics; Immunology; Impairment; Individual; Inflammatory; Intervention; Investigation; Leukocytes; Mediating; Mentorship; Modality; Mutate; Mutation; Myeloid Cells; Outcome; Output; Pathogenicity; Pathway interactions; Patients; Pattern; Physicians; Population; Recurrent disease; Relapse; Research; Research Personnel; Residual state; Risk; Sampling; Scientist; Shapes; Signal Transduction; Somatic Mutation; Stem cell transplant; T-Cell Development; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Time; Toxic effect; Training; Transplant Recipients; Transplantation; Work; adverse outcome; age related; base; cancer cell; career; career development; cell type; curative treatments; cytokine; cytopenia; disorder risk; exhaustion; experimental study; graft failure; graft function; graft vs leukemia effect; hematopoietic cell transplantation; improved; improved outcome; insight; leukemia relapse; mutant; novel; novel strategies; novel therapeutic intervention; post-transplant; pressure; relapse risk; single cell technology; success

PROJECT SUMMARY/ABSTRACT Hematopoietic cell transplant (HCT) is an important treatment modality for patients with hematologic malignancy (HM). Its success depends on the ability of donor hematopoietic cells to establish long-term hematopoiesis and immunologically mediated elimination of residual malignant cells. Clonal hematopoiesis (CH) is an age-related condition in which detectable somatic mutations alter the biologic function and inflammatory output of hematopoietic cells, and in non-transplant populations is uniformly associated with adverse outcomes. By studying 1727 HCT donor-recipient pairs, I found that CH in donors is common and that inactivating mutations in the gene DNMT3A are the most frequent alterations. My preliminary data shows that donor DNMT3A-CH is associated with improved global recipient outcomes, mediated by a reduced risk of HM relapse, but also increases the risk of graft failure in a subset of recipients. Based on these data and the known function of DNMT3A in hematopoietic cells, I hypothesize that the effects of donor DNMT3A-CH I observe in HCT recipients are due to engraftment of DNMT3A-mutated long-term hematopoietic stem cells and subsequent altered function in mature DNMT3A-mutant leukocyte subsets, particularly T cells. To test this hypothesis, I propose the following two aims: (1) Determine the effect of DNMT3A-CH on normal and impaired hematopoiesis following HCT. I will use genomic, immunophenotypic, and single-cell technologies to define the characteristics, including cellular compartment, of donor DNMT3A mutations that engraft in recipients. I will then focus on elucidating the biology of graft failure developing in recipients of donor DNMT3A-CH. (2) Define the effect of DNMT3A-CH in donor- engrafted T-cells after transplantation. I will use genomic, immunophenotypic, and single-cell techniques to determine the effect of donor DNMT3A mutations on T-cell composition and function in recipients after transplantation, focusing specifically on how DNMT3A mutations modulate the development of T-cell exhaustion. I will then specifically assess how donor DNMT3A mutations in T cells affect the pathways of immune evasion utilized by relapsing cases of acute myeloid leukemia. The information gained from these studies will provide new insights into the biology of post-transplant hematopoiesis and immune surveillance that could have profound implications for donor selection and strategies to augment the graft-versus-leukemia effect. In concert with the proposed experiments, I have outlined a five-year career development plan aimed at the goal of becoming an independent investigator in translational transplant research. I have assembled an advisory committee of globally recognized experts in hematopoiesis, transplant immunology, and biostatistics, to provide experimental input and specific training in these fields. Dana-Farber Cancer Institute, which harbors an outstanding research community and has a long track record for successful mentorship of independent physician scientists, is an ideal environment for completion of these experiments and realization of my short and long-term career goals.

项目摘要/摘要 造血细胞移植（HCT）是血液恶性肿瘤患者的重要治疗方式 （HM）。它的成功取决于供体造血细胞建立长期造血和的能力 免疫学介导的消除残留恶性细胞。克隆造血（CH）是与年龄有关的 可检测到的体细胞突变改变了生物学功能和炎症输出的条件 造血细胞和非移植群中的种群均匀地与不良结果相关。经过 研究1727 HCT供体 - 重点对，我发现供体中的CH很常见，并且灭活突变 在基因中，dnmt3a是最常见的改变。我的初步数据表明，供体DNMT3A-CH是 与改善的全球接受者结果相关的结果，这是由于HM复发的风险降低而介导的 增加了受体一部分的移植失败风险。基于这些数据和已知功能 造血细胞中的DNMT3A，我假设供体DNMT3A-CH的作用在HCT接受者中观察到 是由于植入DNMT3A突变的长期造血干细胞，随后的功能改变了 在成熟的DNMT3A突变体白细胞亚群中，尤其是T细胞。为了检验这一假设，我提出以下内容 两个目的：（1）确定DNMT3A-CH对HCT后正常和受损造血的影响。我会 使用基因组，免​​疫表型和单细胞技术来定义特征，包括细胞 车厢，供接受者植入的供体DNMT3A突变。然后，我将专注于阐明生物学 供体DNMT3A-CH的接收者的移植失败。 （2）定义DNMT3A-CH对供体的影响 - 移植后植入T细胞。我将使用基因组，免​​疫表型和单细胞技术 确定供体DNMT3A突变对在接受者中T细胞组成和功能的影响 移植，专门针对DNMT3A突变如何调节T细胞耗尽的发展。 然后，我将特别评估T细胞中的供体DNMT3A突变如何影响免疫逃避的途径 通过复发性急性髓样白血病的病例来使用。从这些研究中获得的信息将提供 对移植后造血和免疫监测的生物学的新见解，可能具有深刻的 对捐助者选择的含义和增强移植物与白血病效应的策略。与 拟议的实验，我概述了一项为期五年的职业发展计划，目的是成为一个 转化移植研究的独立研究者。我已经组建了一个全球咨询委员会 公认的造血，移植免疫学和生物统计学专家，以提供实验输入 以及这些领域的具体培训。达纳 - 法伯癌症研究所（Dana-Farber Cancer Institute），该研究所拥有出色的研究 社区，并在成功的独立医师科学家的成功指导方面拥有悠久的记录，这是理想的 完成这些实验的环境以及实现我的短期和长期职业目标的环境。