Comprehensive analysis of oncogenic transcriptional factor Evi-1.

Evi-1是SET/PR结构域转录因子家族的成员，其不适当的表达会导致白血病转化。从Evi-1基因产生两种不同的替代形式，Evi-1a和Evi-1c。虽然Evi-1a(PR缺失形式)被广泛认为是一种癌蛋白，但Evi-1c(PR缺失形式)在白血病发生中的作用尚未阐明。在本研究中，我们发现Evi-1a形成同源低聚物，而Evi-1c仅以单体形式存在。值得注意的是，Evi-1c已经失去了与ctBP相互作用和抑制转化生长因子-β信号的能力。这些结果表明，寡聚化有助于Evi-1的致癌潜力。接下来，我们建立了Evi-1突变小鼠，以研究Evi-1在体内的造血和白血病发生中的作用。在这些小鼠身上，我们发现Evi-1以剂量依赖的方式调节胚胎发育期间和成人中的造血干细胞的增殖能力。相比之下，Evi-1对于血细胞谱系承诺是必不可少的。我们进一步证明，在MLL/ENL或E2A/HLF转化的白血病细胞中，Evi-1的破坏会导致其增殖活性的显著丧失。这些结果表明，EVI-1是正常细胞和白血病细胞增殖的关键调节因子。

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.