Comprehensive analysis of oncogenic transcriptional factor Evi-1.

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Evi-1 is a member of the SET/PR domain family of transcription factors whose inappropriate expression leads to leukemic transformation. Two distinct alternative forms, Evi-1a and Evi-1c, are generated from the Evi-1 gene. Although Evi-1a (PR-absent form) is widely recognized as an oncoprotein, a role for Evi-1c (PR-containing form) in leukemogenesis has not been elucidated. In this study, we showed that Evi-la forms homo-oligomers while Evi-1c exclusively exists as a monomer. Remarkably, Evi-1c has lost the ability to interact with CtBP, and to repress TGF-β signaling. These results indicate that oligomeraization contributes to the oncogenic potential of Evi-1.Next, We created Evi-1 mutant mice to investigate the in vivo role of Evi-1 in hematopoiesis and leukemogenesis. Using these mice, we showed that Evi-1 regulates proliferative capacity of hematopoietic stem cells in a dose-dependent manner both during embryogenesis and in adults. In contrast, Evi-1 is dispensable for blood cell lineage commitment. We further demonstrated that disruption of Evi-1 in leukemic cells transformed by MLL/ENL or E2A/HLF leads to significant loss of their proliferative activity. These results suggest that Evi-1 is a critical regulator for the proliferation of normal and leukemic cells.