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.

项目摘要/摘要 候选人：劳博士具有高度积极性，而且有资格从事独立职业 肿瘤学领域的学术身体科学家。她受到改善护理的强烈渴望的驱使 患有血液系统恶性肿瘤的患者，了解护理的进步只会 通过对驱动这些疾病的潜在机制进行深入研究。它已经变成了 越来越清楚的表观遗传失调极大地有助于血液学的起源 疾病，但是，基本机制知之甚少。 Rau博士旨在建立 独立研究计划的重点是理解这些表观扰动的目的 最终影响了血液系统恶性肿瘤患者的护理方式。 研究职业发展计划：Rau博士将利用一系列教育和研究资源 得克萨斯州医疗中心加强了她的研究职业发展。在贝勒学院 医学（BCM）生物医学科学研究生课程，她将参加与她的研究相关的课程 包括转化癌的生物学，生物信息学和计算机辅助发现方法。 Rau Will博士 在玛格丽特·古德尔（Margaret Goodell）博士的指导下继续她的高产研究培训 国际认可的干细胞生物学家，她的心理技能同样受到认可。劳博士 精湛的咨询委员会将继续指导她在正式会议期间的研究和职业发展 和一对一的互动。 BCM和她的部门通过确保她的职业发展投资 无论获得该或其他职业发展奖项如何，有75％的研究时间都保护了研究时间。 研究项目：DNMT3A突变在急性髓样白血病（AML）中很常见，并预示了较差的 预后。 Rau博士观察到DNMT3A - / - Murine HSC过表达组蛋白3，赖氨酸79（H3K79） 甲基转移酶DOT1L，导致假设DOT1L可能在 DNMT3A突变AML，由Rau博士生成的广泛初步数据支持。她会在这里 通过检查dot1l-knockdown对DNMT3A - / - HSC中H3K79ME的精确作用 使用鼠模型的DNA甲基化，基因表达和恶性转化。她还将检查 人类AML细胞用于H3K79ME，DNA甲基化和基因表达之间的相互作用，并确定 通过映射，DOT1L抑制作用在DNMT3A突变的AML中发挥治疗效率的机制 通过DOT1L抑制剂处理，H3K79ME，DNA甲基化和基因表达的变化。这项工作将 大大增强对DNMT3A介导的白血病的发病机理的理解，并将提供 有关DNA甲基化与Hisstone修饰之间相互作用的关键信息 血液系统恶性肿瘤的发病机理更广泛。因此，该项目将成为一个强大的 劳博士将在其上建立她独立的研究生涯。