Oncogenes involved in acute myeloid leukemia development

描述(由申请人提供)：本提案的目标是识别和表征在急性髓系白血病(AML)患者中表达的新的癌基因。这项提议的设计是为了让候选人在学术环境中独立从事基础癌症研究，重点是白血病。在北卡罗来纳大学教堂山分校钱宁·德尔博士的实验室工作，为他的职业生涯奠定了良好的基础。在德博士的更多指导下，候选人将利用德博士的实验室和北卡罗来纳大学教堂山分校提供的杰出资源，为独立的研究生涯奠定科学基础。这项研究提案的前两个具体目标集中在描述一种新的RAS激活剂RasGRP4，它是由候选的AML新癌基因确定的。RasGRP4主要在髓系细胞中表达，提示它在这些细胞中具有特定的作用。在小鼠中靶向破坏RasGRP4基因将被用来表征RasGRP4的正常功能。将分析这些小鼠的造血系统的发育，以及可能利用RasGRP4的信号转导途径。通过将北卡罗来纳大学教堂山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相结合，这些研究提供了一个极好的机会来扩大候选人的技术能力(例如，动物模型开发和原代造血细胞分析)。这项提议的最后一个目标将在该奖项的独立阶段启动，目的是对急性髓细胞白血病的癌基因进行更多的筛查。AML的形成需要两种突变：一种是诱导细胞增殖和存活，另一种是抑制分化。AML1-ETO和Cbfb-MYH11是AML中两个常见的癌基因，但不足以诱发白血病。这项建议描述了识别AML患者所需突变的实验，这些AML患者的白血病细胞含有这些融合蛋白，这些融合蛋白与这些癌基因协同工作，并识别这两类AML癌基因的成员。这将为扩大和改进旨在确定急性髓系白血病新癌基因的战略提供机会。总而言之，这项提议为候选人完成成为独立研究员的培训提供了一个极好的机会。

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.