Tribbles proteins, of which three mammalian homologues are known, are poorly characterized proteins thathave been implicated in protein degradation. They are characterized by a central non-functional kinase-likedomain. We recently identified Tribbles homologue 2 (Trib2) as a Notch-regulated transcript in leukemic cellsundergoing growth arrest. To investigate the in vivo function of Trib2, mice were reconstituted withhematopoietic stem cells retrovirally expressing Trib2. All Trib2 reconstituted mice developed clonal acutemyelogenous leukemia (AMI) that could be serially transferred. Because Drosophila Tribbles negativelyregulates slbo, the Drosophila homologue of C/EBP, we investigated the relationship between Trib2 andC/EBPa. We identified Trib2 in a complex with C/EBPa, which resulted in C/EBPa degradation. Todetermine the relevance of our findings to human AML, a survey of Trib2 mRNA expression in human AMIpatient samples identified elevated Trib2 expression in a subset of samples. Together, our data identify Trib2as an oncogene in the pathogenesis of AML that functions by inactivating C/EBPa. The goals of thisproposal are to determine the mechanism by which Trib2 induces C/EBPa degradation, determine themechanism by which Trib2 induces AML, to identify the Trib2-expressing hematopoietic progenitors thatinitiate AML, and to identify genes that cooperate with Trib2 in the pathogenesis of AML. These studiesshould not only lead to a better understanding of the pathogenesis of AML, but should have directtranslational utility as they will identify new targets for diagnosing and treating AML. Experiments describedin this project will greatly benefit from extensive interactions with the other Project Leaders and their projectsand will also make extensive use of the scientific cores.
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