Oncogenes involved in acute myeloid leukemia development

描述（由申请人提供）：本提案的目的是鉴定和表征急性髓性白血病（AML）患者中表达的新型癌基因。本提案的设计是让候选人在学术环境中从事基础癌症研究的独立职业，重点是白血病。在北卡罗莱纳大学教堂山分校钱宁·德博士的实验室工作为我的职业生涯奠定了良好的基础。在Dr. Der的指导下，候选人将利用Dr. Der的实验室和北卡罗来纳大学教堂山分校提供的优秀资源，为独立的研究生涯奠定坚实的科学基础。该研究计划的前两个具体目标集中在表征一种新的Ras激活剂RasGRP4，该激活剂由候选药物在AML中筛选新的致癌基因中鉴定出来。RasGRP4主要在髓系细胞中表达，这表明它在这些细胞中具有特定的作用。在小鼠中靶向破坏RasGRP4基因将用于表征RasGRP4的正常功能。我们将分析这些小鼠造血系统的发育以及可能利用RasGRP4的信号转导途径。通过结合北卡罗来纳大学教堂山分校动物模型设施提供的资源和Der博士在Ras信号转导方面的专业知识，这些研究为扩展候选人的技术技能（例如，动物模型开发和原代造血细胞分析）提供了绝佳的机会。该提案的最后一个目标，将在该奖项的独立阶段启动，是对AML中的癌基因进行额外筛选。AML的形成需要两类突变：一类诱导细胞增殖和存活，另一类抑制分化。AML中常见的两种致癌基因AML1-Eto和CBFb-MYH11并不足以诱导白血病。该提案描述了在白血病细胞中含有这些融合蛋白的AML患者中表达所需突变的实验，这些突变与这些癌基因合作，并且还鉴定了两类AML癌基因的成员。这将为扩大和改进AML中识别新癌基因的策略提供机会。综上所述，这个提案为候选人提供了一个很好的机会来完成他的训练，成为一名独立的研究员。

DESCRIPTION (provided by applicant): The goal of this proposal is to identify and characterize novel oncogenes expressed in patients with acute myeloid leukemia (AML). The design of this proposal is to position the candidate for an independent career in basic cancer research, with a focus on leukemia, in an academic environment. Working in Dr. Channing Der's laboratory at the University of North Carolina at Chapel Hill has provided an excellent foundation for this career. With a little more guidance from Dr. Der, the candidate will utilize the outstanding resources that Dr. Der's laboratory and the University of North Carolina at Chapel Hill provide, in order to solidify the scientific basis for an independent career in research. The first two specific aims of this research proposal focus on characterizing a novel activator of Ras, RasGRP4, identified by the candidate in a screen for novel oncogenes in AML. RasGRP4 is primarily expressed in myeloid cells suggesting it has a specific role in these cells. Targeted disruption of the gene for RasGRP4 in mice will be utilized to characterize the normal function of RasGRP4. The development of the hematopoietic system of these mice will be analyzed along with signal transduction pathways that may utilize RasGRP4. These studies represent an excellent opportunity to expand the candidate's technical repertoire (e.g., animal model development and analyses of primary hematopoietic cells), by combining the resources provided by the UNC Chapel Hill animal model facility and Dr. Der's expertise on Ras signal transduction. The last aim of this proposal, which will be initiated in the independent phase of the award, is to perform additional screens for oncogenes in AML. AML formation requires two classes of mutations: one that induces cell proliferation and survival, and one that inhibits differentiation. AML1-Eto and CBFb-MYH11, two common oncogenes in AML, are not sufficient to induce leukemia. This proposal describes experiments to identify required mutations, expressed in AML patients whose leukemic cells harbor these fusion proteins, that cooperate with these oncogenes and also to identify members of both classes of AML oncogenes. This will provide an opportunity to expand and improve strategies aimed at identifying novel oncogenes in AML. In summary, this proposal provides an excellent opportunity for the candidate to complete his training to become an independent researcher.