Oncogenes involved in acute myeloid leukemia development

描述（由申请人提供）： 本提案的目标是鉴定和表征急性髓性白血病（AML）患者中表达的新癌基因。 该提案的设计是将候选人定位为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。 在查佩尔山的北卡罗来纳州大学的Channing Der博士的实验室工作为这一职业提供了良好的基础。 在Der博士的指导下，候选人将利用Der博士的实验室和查佩尔山的北卡罗来纳州大学提供的优秀资源，以巩固独立研究职业的科学基础。 这项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RasGRP 4，该激活剂是由候选人在AML中筛选新癌基因时确定的。 RasGRP 4主要在骨髓细胞中表达，表明其在这些细胞中具有特定作用。 将利用小鼠中RasGRP 4基因的靶向破坏来表征RasGRP 4的正常功能。 将沿着可能利用RasGRP 4的信号转导途径来分析这些小鼠的造血系统的发育。 这些研究是一个很好的机会，以扩大候选人的技术剧目（例如，动物模型开发和初级造血细胞的分析），通过结合由美国查佩尔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。 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的筛查。 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中两种常见的癌基因AML 1-Eto和CBFb-MYH 11不足以诱导白血病。 该提案描述了鉴定所需突变的实验，所述突变在其白血病细胞含有这些融合蛋白的AML患者中表达，所述突变与这些癌基因合作，并且还鉴定两类AML癌基因的成员。 这将提供一个机会，以扩大和改善战略，旨在确定新的癌基因在AML。 总而言之，这份建议书为候选人提供了一个极好的机会，使其能够完成培训，成为一名独立的研究人员。

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.