The Function of Tribbles in the Pathogenesis of AML

Tribble蛋白，其中有三个哺乳动物同源蛋白已知，是一种特性不佳的蛋白质， 与蛋白质降解有关。它们的特征是一种中心的非功能激酶样蛋白 域。我们最近在白血病细胞中发现Tribble同源基因2(Tribble Homologue 2，Trib2)是一种Notch调控的转录本 正在经历增长停滞。为了研究Trib2在体内的功能，将小鼠重组为 逆转录病毒表达Trib2的造血干细胞。所有Trib2重组小鼠均出现克隆性急性淋巴细胞白血病 可连续转移的髓系白血病(AMI)。因为果蝇的负面摩擦 调节C/EBP的果蝇同源物SLBO，我们研究了Trib2与EBP的关系 C/EBPA。我们在与C/EBPA的复合物中发现了Trib2，它导致了C/EBPA的降解。至 确定我们的发现与人类急性髓细胞白血病的相关性，一项关于人类急性心肌梗死患者Trib2基因表达的调查 患者样本在样本子集中发现Trib2表达升高。总而言之，我们的数据确定了Trib2 作为一种癌基因，在AML的发病机制中通过灭活C/EBPA发挥作用。这样做的目的是 建议确定Trib2诱导C/EBPA降解的机制，确定 TRIB2诱导AML的机制，鉴定表达TRIB2的造血祖细胞 启动AML，并寻找在AML发病机制中与Trib2协同作用的基因。这些研究 不仅应该导致对AML发病机制的更好的了解，而且应该有直接的 翻译效用，因为他们将确定诊断和治疗急性髓细胞白血病的新靶点。所描述的实验 将从与其他项目负责人和他们的项目的广泛互动中受益匪浅 并将广泛利用科学核心。

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.