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

• 批准号: 10596588
• 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
• 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/10596588
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Area; Bioinformatics; Biological Assay; Bone Marrow; Bone Marrow Cells; CCAAT-Enhancer-Binding Protein-alpha; Cells; ChIP-seq; Chromatin; Clonal Evolution; Committee Members; Core-Binding Factor; Cytokine Receptors; DNA Binding; Data; Dedications; 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; KDM1A gene; Laboratories; 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; core binding factor alpha; 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; receptor; recruit; small hairpin RNA; synergism; t(8; 21)(q22; q22); targeted agent; targeted cancer therapy; targeted treatment; transcription factor; transcriptome sequencing

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.

项目总结 急性髓系白血病(AML)最终是突变逐步获得的结果 导致恶变。改变表观基因组的突变发生在疾病的早期 而激活信号通路的突变发生在较晚的时间。我已经开发出一种 可以在体内直接操纵突变顺序的实验系统。使用这个系统，我 证明转录因子CCAAT增强子结合蛋白α(CEBPA)的突变 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 发展。在目标1中，我将调查表观相似的核心结合因子(CBF)AML是否也 证明了顺序依赖与共生的信号突变。我还将建立 突变顺序对发育中的造血祖细胞表观遗传格局的影响。 在目标2中，我将评估赖氨酸去甲基酶1作为CSF3R/CEBPA突变体AML的驱动因素的作用 通过表观遗传学特征和功能丧失研究。在目标3中，我将确定新的治疗方法 逆转CEBPA/CBF AML中出现的表观遗传功能障碍并恢复 急性髓系白血病细胞的分化潜能。 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 基因组学和靶向治疗。我将继续在博士的实验室进行有指导的研究。 布莱恩·德鲁克，靶向癌症治疗领域的先驱，奈特癌症中心主任 研究所。我将接受癌症表观遗传学和生物信息学分析领域的额外培训。 在我的导师委员会成员Lucia Carbone博士和Joshi Alumkal博士的指导下 还有我和我的合作者希沙姆·穆罕默德博士。我会继续看望血液病患者 恶性每周半天在门诊，剩下的时间都致力于研究。 德鲁克博士和我的指导团队将帮助我获得我的第一笔R01拨款，并在 过渡到运营一个独立的研究小组。