Epigenetics of Mutation-Order in Acute Myeloid Leukemia

急性髓系白血病突变顺序的表观遗传学

基本信息

批准号：
10379071
负责人：
Theodore Paul Braun
金额：
$ 16.25万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10379071
关键词：
Acute Myelocytic Leukemia Acute leukemia Area Bioinformatics Biological Assay Bone Marrow Bone Marrow Cells CCAAT-Binding Factor CCAAT-Enhancer-Binding Protein-alpha Cells ChIP-seq Chromatin Clonal Evolution Committee Members Core-Binding Factor Cytokine Receptors DNA Binding Data Dependence Development Disease Enhancers Epigenetic Process FLT3 gene Flow Cytometry Functional disorder Goals Grant Granulocyte Colony-Stimulating Factor Receptors Hematologic Neoplasms Hematopoietic Hematopoietic stem cells Human In Vitro Individual Institutes KDM1A gene Laboratories Light Lysine MYH11 gene Malignant - descriptor Malignant Neoplasms Mentors Mentorship Modeling Mus Mutation Myelogenous Myeloproliferative disease Outpatients Participant Patients Phenotype Process Property Research Research Personnel Role Running Sampling Signal Pathway Signal Transduction Sum System Therapeutic Therapeutic Intervention Time Training Work cytotoxicity driver mutation epigenetic profiling epigenetic therapy epigenome experimental study gene therapy in vivo inhibitor knock-down leukemia loss of function mutant novel novel therapeutic intervention novel therapeutics overexpression prevent recruit small hairpin RNA synergism t(8 21)(q22 q22)targeted agent targeted cancer therapy targeted treatment transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY Acute myeloid leukemia (AML) develops as a result of the stepwise acquisition of mutations ultimately resulting in malignant transformation. Mutations that alter the epigenome occur early in disease development, while mutations that activate signaling pathways occur later. I have developed an experimental system in which mutation order can be directly manipulated in vivo. Using this system, I demonstrate that mutations in the transcription factor CCAAT enhancer binding protein alpha (CEBPA) must occur prior to mutations in Colony Stimulating Factor 3 Receptor (CSF3R) in order for leukemia to develop. In Aim 1, I will investigate whether the epigenetically similar core binding factor (CBF) AML also demonstrates order dependence with co-occurring signaling mutations. I will also establish the consequences of mutation order on the epigenetic landscape of developing hematopoietic progenitors. In Aim 2, I will evaluate the role of lysine demethylase 1 as a driver of CSF3R/CEBPA mutant AML through epigenetic profiling and loss of function studies. In Aim 3, I will identify novel therapeutic approaches that reverse the epigenetic dysfunction seen in CEBPA/CBF AML and restore the differentiation potential of AML blasts. My goal is to become a successful independent investigator and a leader in the field of leukemia genomics and targeted therapy. I will continue to conduct mentored research in the Laboratory of Dr. Brian Druker, a pioneer in the field of targeted cancer therapy and Director of the Knight Cancer Institute. I will undertake additional training in the area of cancer epigenetics and bioinformatic analysis with the guidance of my mentorship committee members Dr. Lucia Carbone and Dr. Joshi Alumkal as well as my and collaborator Dr. Hisham Mohammed. I will continue to see patients with hematologic malignancy ½ day weekly in the outpatient setting with the remainder of my time dedicated to research. Dr. Druker and my mentorship team will assist me in obtaining my first R01 grant and in navigating the transition to running an independent research group.

项目概要急性髓系白血病 (AML) 是最终突变逐步获得的结果导致疾病早期发生改变表观基因组的突变。发育，而激活信号通路的突变发生在后来。使用该系统可以在体内直接操纵突变顺序的实验系统。证明转录因子 CCAAT 增强子结合蛋白 α (CEBPA) 发生突变必须在集落刺激因子 3 受体 (CSF3R) 突变之前发生，才能使白血病发生在目标 1 中，我将研究表观遗传相似的核心结合因子 (CBF) AML 是否也存在。证明了与同时发生的信号突变的顺序依赖性。突变顺序对发育中的造血祖细胞的表观遗传景观的影响。在目标 2 中，我将评估赖氨酸脱甲基酶 1 作为 CSF3R/CEBPA 突变 AML 驱动因素的作用通过表观遗传分析和功能丧失研究，我将在目标 3 中确定新的治疗方法。逆转 CEBPA/CBF AML 中观察到的表观遗传功能障碍并恢复 AML 母细胞的分化潜力。我的目标是成为一名成功的独立研究者和白血病领域的领导者我将继续在博士的实验室进行指导研究。 Brian Druker，癌症靶向治疗领域的先驱者、Knight Cancer 主任我将在癌症表观遗传学和生物信息分析领域接受额外的培训。在我的导师委员会成员 Lucia Carbone 博士和 Joshi Alumkal 博士的指导下我和我的合作者 Hisham Mohammed 医生将继续看诊血液病患者。每周 ½ 天在门诊治疗恶性肿瘤，其余时间致力于研究。 Druker 博士和我的导师团队将协助我获得第一笔 R01 资助并顺利完成过渡到运行一个独立的研究小组。