The Requirement for Trib2 in the Maintenance of Acute Myeloid Leukemia

Trib2 在维持急性髓系白血病中的需要

• 批准号: 8554753
• 负责人: Will H. Bailis
• 金额: $ 2.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-06 至 2015-07-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554753
• 关键词: Acute Myelocytic Leukemia; Alleles; Apoptosis; Biological Assay; CCAAT-Enhancer-Binding Proteins; Cell Differentiation process; Cell Line; Cells; Collection; Data; Differentiation Therapy; Down-Regulation; Event; Exhibits; Gene Expression Regulation; Goals; Growth; Hematopoietic; Homologous Gene; Human; In Vitro; Laboratories; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Metabolism; Modeling; Mus; Myelogenous; Oncogenes; Oncogenic; Pathogenesis; Patients; Phenotype; Play; Publishing; Role; Sampling; Signal Transduction; Technology; Testing; Tissues; Work; cancer cell; cancer therapy; cancer type; design; inhibitor/antagonist; leukemia; malignant phenotype; melanoma; mouse model; neoplastic cell; self-renewal; small hairpin RNA; therapeutic development; tumor

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.

描述（由适用提供）：首先证明Tribbles同源物2（Trib2）是AML中的癌基因，随后已被确定为黑色素瘤和肺癌中的癌基因。尽管Trib2能够在小鼠模型中诱导AML，但不知道是否需要持续的Trib2表达来维持转化的表型。我的目标是确定Trib2在维持AML转换表型中的功能。我们发表的初步数据表明，扭转障碍物抑制AML细胞系的分化并部分通过阻断C/EBP促进白血病。因此，靶向依赖于Trib2的AML中的Trib2将促进肿瘤细胞的分化，这证明了一种成功治疗AML的策略，并且这项研究的长期目标是为Trib2抑制剂的设计用于治疗癌症的设计，该研究旨在在癌症的异常基因调节中理解Trib2，并在癌症中的范围内确定其在癌症中的作用，并将在癌症中确定癌症的自我群体，并在癌症中差异化。将通过创建一个可以有条件调节的Trib2诱导的AML的鼠模型来测试Trib2在维持AML身份方面的需求。我们将通过使用SHRNA对TRIB2的敲低来确定表达高水平Trib2的人类AML细胞系和原代AML样品是否对Trib2抑制敏感的人类AML细胞系和原代AML样品是否将研究扩展到人类细胞。通过证明与部落相关的AML需要持续的Trib2活动，我们的研究将验证TRIB2作为治疗的靶标，该发现可能会扩展到暴露于Trib2失调的其他多种类型的癌症。