The Function of Tribbles in the Pathogenesis of AML

Tribbles蛋白，其中三种哺乳动物同源物是已知的，是表征不佳的蛋白质， 与蛋白质降解有关。它们的特征是一种中枢非功能性激酶样 域我们最近发现Tribbles同源物2（Trib2）是白血病细胞中Notch调控的转录本 正在经历生长停滞为了研究Trib2的体内功能，将小鼠用 逆转录病毒表达Trib2的造血干细胞。所有Trib2重建小鼠均发生克隆性急性 骨髓性白血病（AMI），可以连续转移。因为果蝇的摩擦是负面的 调节sLbo，果蝇同源的C/EBP，我们研究了Trib2和 C/EBPa。我们在与C/EBPa的复合物中鉴定了Trib2，这导致C/EBPa降解。到 确定我们的研究结果与人类AML的相关性，一项对人类AMI中Trib2 mRNA表达的调查 患者样品在样品亚组中鉴定出升高的Trib2表达。总之，我们的数据确定了Trib2 作为AML发病机制中的癌基因，其通过使C/EBP α失活而起作用。这个的目标 建议是确定Trib2诱导C/EBPa降解的机制，确定 Trib2诱导AML的机制，以鉴定表达Trib2的造血祖细胞， 启动AML，并鉴定在AML发病机制中与Trib2合作的基因。这些研究 这不仅有助于更好地了解AML的发病机制，而且还可以直接 因为它们将鉴定诊断和治疗AML的新靶点。述实验 在这个项目中，我将从与其他项目负责人及其项目的广泛互动中受益匪浅 并将广泛利用科学内核。

Tribbles proteins, of which three mammalian homologues are known, are poorly characterized proteins that have been implicated in protein degradation. They are characterized by a central non-functional kinase-like domain. We recently identified Tribbles homologue 2 (Trib2) as a Notch-regulated transcript in leukemic cells undergoing growth arrest. To investigate the in vivo function of Trib2, mice were reconstituted with hematopoietic stem cells retrovirally expressing Trib2. All Trib2 reconstituted mice developed clonal acute myelogenous leukemia (AMI) that could be serially transferred. Because Drosophila Tribbles negatively regulates slbo, the Drosophila homologue of C/EBP, we investigated the relationship between Trib2 and C/EBPa. We identified Trib2 in a complex with C/EBPa, which resulted in C/EBPa degradation. To determine the relevance of our findings to human AML, a survey of Trib2 mRNA expression in human AMI patient samples identified elevated Trib2 expression in a subset of samples. Together, our data identify Trib2 as an oncogene in the pathogenesis of AML that functions by inactivating C/EBPa. The goals of this proposal are to determine the mechanism by which Trib2 induces C/EBPa degradation, determine the mechanism by which Trib2 induces AML, to identify the Trib2-expressing hematopoietic progenitors that initiate AML, and to identify genes that cooperate with Trib2 in the pathogenesis of AML. These studies should not only lead to a better understanding of the pathogenesis of AML, but should have direct translational utility as they will identify new targets for diagnosing and treating AML. Experiments described in this project will greatly benefit from extensive interactions with the other Project Leaders and their projects and will also make extensive use of the scientific cores.