Tribbles Homolog 2 (Trib2) Inactivates C/EBPalpha and Causes Acute Myelogenous Leukemia.

Trib2 is a member of the Trib family of serine/threonine kinase-like proteins (Trib1, Trib2, Trib3), whose function in hematopoiesis is not documented. To investigate the effects of Trib2 in hematopoietic progenitors, mice were reconstituted with hematopoietic stem cells retrovirally expressing Trib2. Trib2-reconstituted mice uniformly developed fatal transplantable acute myelogenous leukemia (AML), with a median survival of 179 days. Retroviral Trib2 expression in hematopoietic stem cells perturbed myeloid development, enhanced progenitor proliferation, and directly inhibited the function of C/EBPα, a critical transcription factor that is frequently dysregulated in AML. Furthermore, an analysis of microarray data generated from 285 AML patient samples identified elevated Trib2 expression in a distinct subset of patients in a cluster with a high frequency of C/EBPα mutations. In mechanistic studies, we found that Trib2 associated with and led to the proteasomal-dependent degradation of C/EBPα. To determine the structural requirements for Trib2 to inhibit C/EBPα, and to induce AML, we have initiated a structure/function analysis of Trib2. Together, our data identify Trib2 as a novel oncogene that induces AML through a mechanism involving inactivation of C/EBPα. The identification of Trib2 as potent leukemogen points to new pathogenic mechanisms and possible therapeutic opportunities in this aggressive cancer, which is not currently curable in the majority of patients.