Epigenetics of Mutation-Order in Acute Myeloid Leukemia

项目摘要 急性髓细胞白血病（AML）的发展是逐步获得突变的结果， 导致恶性转化。改变表观基因组的突变发生在疾病的早期 发育，而激活信号通路的突变发生在以后。我开发了一个 突变顺序可以在体内直接操作的实验系统。使用这个系统，我 证明了转录因子CCAAT增强子结合蛋白α（CEBPA）的突变 必须发生在集落刺激因子3受体（CSF 3R）突变之前， 开发.在目的1中，我将研究表观遗传学相似的核心结合因子（CBF）AML是否也 证明了与共同发生的信号突变的顺序依赖性。我还将建立 突变顺序对发育中的造血祖细胞的表观遗传景观的后果。 在目标2中，我将评估赖氨酸脱甲基酶1作为CSF 3R/CEBPA突变型AML驱动因子的作用。 通过表观遗传分析和功能丧失研究。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 基因组学和靶向治疗。我将继续在博士的实验室进行指导研究。 Brian Druker，靶向癌症治疗领域的先驱，Knight Cancer主任 院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， 以及我的合作者希沙姆·穆罕默德博士我会继续看血液病患者 恶性肿瘤每周半天在门诊设置与我的时间致力于研究的其余部分。 博士德鲁克和我的导师团队将帮助我获得我的第一个R 01赠款，并在导航 过渡到运行一个独立的研究小组。

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.