DEFINING THE ROLE OF DOT1L IN DNMT3A-MUTANT LEUKEMIA

定义 DOT1L 在 DNMT3A 突变白血病中的作用

• 批准号: 9447141
• 负责人: Rachel E Rau
• 金额: $ 16.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447141
• 关键词: Acute Myelocytic Leukemia; Adult; Advisory Committees; Automobile Driving; Bioinformatics; Biological Assay; Cancer Biology; Caring; Cell Line; Cells; ChIP-seq; Child; Complex; Computer Assisted; DNA Methylation; DNA Modification Methylases; DNA Sequence Alteration; DNMT3a; Data; Development; Development Plans; Disease; Dominant-Negative Mutation; Drug Targeting; Dysmyelopoietic Syndromes; Enrollment; Epigenetic Process; Evaluation; Foundations; Gene Expression; Genes; Genetic; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Histones; House mice; Human; Intention; International; Investigation; K-Series Research Career Programs; Lesion; Light; Lysine; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Medical center; Medicine; Mentors; Mentorship; Methods; Methylation; Methyltransferase; Mus; Mutation; Myeloproliferative disease; Pathogenesis; Patient Care; Patients; Pharmacology; Physicians; Play; Premalignant; Property; Proteins; Research; Research Project Grants; Research Training; Resources; Role; Sampling; Science; Scientist; Stem cells; System; T-Cell Leukemia; Testing; Texas; Time; Treatment Efficacy; Work; career; career development; college; histone modification; human DNA; human disease; improved; inhibitor/antagonist; interest; knock-down; leukemia; leukemia/lymphoma; leukemogenesis; meetings; mouse model; mutant; oncology; outcome forecast; overexpression; programs; research and development; self-renewal; skills; small hairpin RNA; telomere

PROJECT SUMMARY/ABSTRACT The Candidate: Dr. Rau is highly motivated and exceptionally qualified to pursue a career as an independent academic physician-scientist in the field of oncology. She is driven by an intense desire to improve the care of patients afflicted with hematologic malignancies, with the understanding that advances in care will arise only through deep investigation of the underlying mechanisms that drive these diseases. It has become increasingly clear that epigenetic dysregulation contributes substantially to the genesis of hematologic diseases, however the underlying mechanisms are poorly understood. Dr. Rau aims to establish an independent research program focused on understanding these epigenetic perturbations with the intention of ultimately impacting the way patients with hematologic malignancies are cared for. Research Career Development Plan: Dr. Rau will utilize an array of educational and research resources in the Texas Medical Center to strengthen her research career development. Within the Baylor College of Medicine (BCM) graduate programs in biomedical sciences, she will enroll in courses relevant to her research including translational cancer biology, bioinformatics, and computer aided discovery methods. Dr. Rau will continue her highly productive research training under the mentorship of Dr. Margaret Goodell, an internationally recognized stem cell biologist who is equally recognized for her mentoring skills. Dr. Rau's superb advisory committee will continue to guide her research and career development during formal meetings and one-on-one interactions. BCM and her department have invested in her career development by assuring 75% protected time for research regardless of receipt of this or other career development award. Research Project: DNMT3A mutations are common in acute myeloid leukemia (AML) and portend a poor prognosis. Dr. Rau observed that Dnmt3a–/– murine HSCs overexpress the histone 3, lysine 79 (H3K79) methyltransferase, Dot1l, leading to the hypothesis that DOT1L may play a central role in the pathogenesis of DNMT3A-mutant AML, which is supported by extensive preliminary data generated by Dr. Rau. Here, she will determine the precise role of H3K79me in Dnmt3a–/– HSCs by examining the impact of Dot1l-knockdown on DNA methylation, gene expression, and malignant transformation using murine models. She will also examine human AML cells for the interplay between H3K79me, DNA methylation and gene expression, and determine the mechanisms by which DOT1L inhibition exerts therapeutic efficacy in DNMT3A-mutant AML by mapping changes in H3K79me, DNA methylation and gene expression with DOT1L inhibitor treatment. This work willl greatly enhance the understanding of the pathogenesis of DNMT3A-mediated leukemia, and will provide critical information about the interations between DNA methylation and histone modifications in the pathogenesis of hematologic malignacies more broadly. Therefore, this project will serve as a strong foundation on which Dr. Rau will build her independent research career.

项目概要/摘要 候选人：Rau 博士积极性很高，并且非常有资格从事独立职业 她是肿瘤学领域的学术医师科学家，强烈渴望改善患者的护理。 患有血液系统恶性肿瘤的患者，了解护理方面的进步只会出现 通过深入研究驱动这些疾病的潜在机制。 越来越清楚的是，表观遗传失调在很大程度上促进了血液学的发生 然而，Rau 博士的目标是建立一种疾病的机制。 独立研究计划的重点是了解这些表观遗传扰动，目的是 最终影响血液恶性肿瘤患者的治疗方式。 研究职业发展计划：Rau 博士将利用一系列教育和研究资源 德克萨斯医学中心加强她在贝勒学院的研究职业发展。 生物医学科学医学（BCM）研究生课程，她将报名参加与她的研究相关的课程 Rau 博士将包括转化癌症生物学、生物信息学和计算机辅助发现方法。 在玛格丽特·古德尔 (Margaret Goodell) 博士的指导下继续她的高度研究和生产培训。 国际公认的干细胞生物学家，劳博士的指导技能也同样得到认可。 卓越顾问委员会将在正式会议期间继续指导她的研究和职业发展 BCM 和她的部门通过确保她的职业发展进行了投资。 无论是否获得此奖项或其他职业发展奖项，75% 的受保护时间用于研究。 研究项目：DNMT3A 突变在急性髓系白血病 (AML) 中很常见，预示着不良预后 Rau 博士观察到 Dnmt3a–/– 小鼠 HSC 过度表达组蛋白 3、赖氨酸 79 (H3K79)。 甲基转移酶 Dot1l，导致了 DOT1L 可能在疾病发病机制中发挥核心作用的假设 DNMT3A 突变型 AML 得到了 Rau 博士生成的大量数据的支持。 通过检查 Dot1l 敲低对 Dnmt3a–/– HSC 的影响，确定 H3K79me 在 Dnmt3a–/– HSC 中的精确作用 她还将使用小鼠模型研究 DNA 甲基化、基因表达和恶性转化。 人类 AML 细胞中 H3K79me、DNA 甲基化和基因表达之间的相互作用，并确定 通过作图研究 DOT1L 抑制在 DNMT3A 突变 AML 中发挥治疗功效的机制 这项工作将通过 DOT1L 抑制剂治疗来改变 H3K79me、DNA 甲基化和基因表达。 极大地增强了对 DNMT3A 介导的白血病发病机制的理解，并将提供 关于 DNA 甲基化和组蛋白修饰之间相互作用的关键信息 因此，该项目将成为更广泛的血液系统恶性肿瘤的发病机制。 Rau 博士将在此基础上建立她的独立研究生涯。