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，其与蛋白质降解有关。它们的特征在于中心非功能性激酶样结构域。我们最近确定Tribbles同源物2（Trib2）作为Notch调控的转录在白血病细胞生长停滞。为了研究Trib2的体内功能，用逆转录病毒表达Trib2的造血干细胞重建小鼠。所有Trib2重组小鼠均发生可连续转移的克隆性急性髓细胞性白血病（AML）。由于果蝇Tribbles负调控slbo，C/EBP的果蝇同源物，我们研究了Trib2和C/EBPa之间的关系。我们在与C/EBPa的复合物中鉴定了Trib2，这导致C/EBPa降解。为了确定我们的发现与人类AML的相关性，对人类AMI患者样本中Trib2 mRNA表达的调查确定了样本子集中Trib2表达升高。总之，我们的数据将Trib2鉴定为AML发病机制中的癌基因，其通过使C/EBPa失活而发挥作用。本提案的目标是确定Trib2诱导C/EBPa降解的机制，确定Trib2诱导AML的机制，鉴定启动AML的表达Trib2的造血祖细胞，并鉴定在AML发病机制中与Trib2合作的基因。这些研究不仅可以更好地了解AML的发病机制，而且还可以直接转化为实用性，因为它们将确定诊断和治疗AML的新靶点。本项目中描述的实验将大大受益于与其他项目负责人及其项目的广泛互动，并将广泛使用科学核心。

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.