Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia.
Tribbles homolog 2 (Trib2) was identified as a downregulated transcript in leukemic cells undergoing growth arrest. To investigate the effects of Trib2 in hematopoietic progenitors, mice were reconstituted with hematopoietic stem cells retrovirally expressing Trib2. Trib2-transduced bone marrow cells exhibited a growth advantage ex vivo and readily established factor-dependent cell lines. In vivo, Trib2-reconstituted mice uniformly developed fatal transplantable acute myelogenous leukemia (AML). In mechanistic studies, we found that Trib2 associated with and inhibited C/EBPalpha. Furthermore, Trib2 expression was elevated in a subset of human AML patient samples. Together, our data identify Trib2 as an oncogene that induces AML through a mechanism involving inactivation of C/EBPalpha.
Keeshan, K; He, Y; Wouters, BJ; Shestova, O; Xu, L; Sai, H; Rodriguez, CG; Maillard, I; Tobias, JW; Valk, P; Carroll, M; Aster, JC; Delwel, R; Pear, WS
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