The Requirement for Trib2 in the Maintenance of Acute Myeloid Leukemia

描述（由申请人提供）：Tribbles同源物2（Trib 2）首次被证明是AML中的癌基因，随后被鉴定为黑色素瘤和肺癌中的癌基因。虽然Trib 2能够在小鼠模型中诱导AML，但不知道持续的Trib 2表达是否是维持转化表型所必需的。我的目标是确定Trib 2在维持AML转化表型中的功能。我们发表的和初步的数据表明，Tribbles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，靶向Trib 2依赖性AML中的Trib 2将促进肿瘤细胞分化，这已被证明是治疗AML的成功策略，并且本研究的长期目标是为用于治疗癌症的Trib 2抑制剂的设计提供信息。所提出的研究寻求在癌症中异常基因调控的背景下理解Trib 2，并将确定其在调节自我更新、增殖、存活、分化和癌细胞代谢。我们将通过建立Trib 2诱导的AML的小鼠模型来测试Trib 2在维持AML身份方面的需求，在该模型中Trib 2表达可以被条件性调节。我们将通过利用shRNA敲低Trib 2来将我们的研究扩展到人类细胞，以确定表达高水平Trib 2的人类AML细胞系和原发性AML样品是否对Trib 2抑制敏感。通过证明Trib-associated AML需要持续的Trib 2活性，我们的研究将验证Trib 2作为治疗靶点，这一发现可能会扩展到表现出Trib 2失调的多种其他类型的癌症。

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.