The Function of Tribbles in the Pathogenesis of AML

Tribble蛋白，其中有三个哺乳动物同源物是已知的，是与蛋白质降解有关的特征不佳的蛋白质。它们的特征是具有一个中心的非功能激酶样结构域。我们最近发现Tribble同系物2(Tribble Homologue 2，Trib2)是在经历生长停滞的白血病细胞中由Notch调控的转录产物。为了研究Trib2在体内的功能，用逆转录病毒表达的造血干细胞重组小鼠。所有重组小鼠均发生了可连续转移的克隆性急性髓系白血病(AML)。由于果蝇Tribble对C/EBP的果蝇同源物slbo具有负性调节作用，因此我们研究了Trib2与C/EBPA的关系。我们在与C/EBPA的复合物中发现了Trib2，它导致了C/EBPA的降解。为了确定我们的发现与人类急性髓细胞白血病的相关性，一项对人类急性心肌梗死患者样本中Trib2基因表达的调查发现，在部分样本中Trib2基因表达升高。总之，我们的数据确认Trib2是AML发病机制中的一个癌基因，它通过失活C/EBPA发挥作用。该方案的目的是确定Trib2诱导C/EBPA降解的机制，确定Trib2诱导AML的机制，确定启动AML的表达Trib2的造血祖细胞，并确定在AML发病机制中与Trib2协同的基因。这些研究不仅应该有助于更好地了解AML的发病机制，而且应该具有直接的翻译作用，因为它们将确定诊断和治疗AML的新靶点。该项目中描述的实验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 (AML) 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.