The Requirement for Trib2 in the Maintenance of Acute Myeloid Leukemia

描述(申请人提供)：Tribble同源基因2(TRIBLUE 2)首先被证明是急性髓细胞白血病的癌基因，随后被鉴定为黑色素瘤和肺癌的癌基因。虽然Trib2能够在小鼠模型中诱导AML，但尚不清楚持续的Trib2表达是否是维持转化表型所必需的。我的目标是确定Trib2在维持AML转化表型方面的功能。我们已发表的和初步的数据表明，Tribble抑制AML细胞系的分化，并促进白血病，部分是通过阻断C/EBP。因此，在依赖Trib2的AML中靶向Trib2将促进肿瘤细胞分化，这已被证明是治疗AML的一种成功策略，本研究的长期目标是为设计用于癌症治疗的Trib2抑制剂提供信息。拟议的研究试图在癌症基因调控异常的背景下了解Trib2，并将确定其在调节自我更新、增殖、存活、分化和癌细胞代谢方面的作用。我们将通过建立Trib2诱导的AML小鼠模型来测试Trib2在维持AML身份方面的需求，在该模型中，Trib2的表达可以被有条件地调节。我们将通过shRNA敲除Trib2来确定高表达Trib2的人AML细胞株和原代AML样本是否对Trib2抑制敏感，从而将我们的研究扩展到人类细胞。通过证明Trib相关的AML需要持续的Trib2活性，我们的研究将验证Trib2作为治疗目标，这一发现可能会延伸到多种其他类型的癌症，表现出Trib2调控失调。 公共卫生相关性：Tribble同系物2(TRIB2)与恶性黑色素瘤、肺癌和急性髓系白血病(AML)有关。我们建议研究急性髓系白血病对Trib2的要求及其作用机制。我们相信，这些研究将进一步加深我们对Trib2在癌症中所起作用的理解，并为治疗Trib2抑制剂的开发提供信息。

DESCRIPTION (provided by applicant): Tribbles homologue 2 (Trib2) was first shown to be an oncogene in AML and subsequently has been identified as an oncogene in melanoma and lung cancer. Although Trib2 is able to induce AML in a mouse model, it is not know if persistent Trib2 expression is necessary to maintain the transformed phenotype. My goal is to identify the function of Trib2 in maintaining the transformed phenotype of AML. Our published and preliminary data show that Tribbles inhibits differentiation of AML cell lines and promotes leukemia, in part, by blocking C/EBP¿. Thus, targeting Trib2 in Trib2-dependent AMLs will promote tumor cell differentiation, which has proven a successful strategy in treating AML, and a long-term goal of this study to inform the design of Trib2 inhibitors for the treatment of cancer The proposed studies seek to understand Trib2 in the context of abnormal gene regulation in cancer and will identify its role in regulating self-renewal, proliferation, survival, differentiaton, and cancer cell metabolism. We will test the requirement for Trib2 in maintaining AML identity by creating a murine model of Trib2-induced AML in which Trib2 expression can be conditionally regulated. We will extend our studies to human cells by employing knockdown of Trib2 by shRNA to determine whether human AML cell lines and primary AML samples that express high levels of Trib2 are sensitive to Trib2 inhibition. By demonstrating that Trib-associated AMLs require persistent Trib2 activity, our studies will validate Trib2 as a target for therapy, a findig that will likely extend to multiple other types of cancers that exhibit Trib2 dysregulation. PUBLIC HEALTH RELEVANCE: Tribbles homologue 2 (Trib2) has been implicated in malignant melanoma, lung cancer, and acute myeloid leukemia (AML). We propose to study the requirements for Trib2 in AML and its mechanism of action. We believe these studies will further our understanding of the role Trib2 plays in cancer and inform the development of therapeutic Trib2 inhibitors.