Integrative elucidation of molecular mechanisms for leukemogenesis: Identification and analyses of mutations with novel categories.

各种表观遗传因素的突变最近在各种血液恶性肿瘤中被发现。我们已经证明TET2、EZH2或ASXL1突变在小鼠骨髓移植（BMT）模型中诱导骨髓增生异常综合征（MDS）样，并且ASXL1突变体通过EZH2/PRC2抑制诱导HoxA9和miR125a的降低在诱导MDS样疾病中起关键作用。我们之前报道过Hes1在CML-BC中起关键作用。我们在这里证明了Hes1通过NFkB激活诱导MMP9表达在CML-BC的进展中起一定作用。此外，我们还证明了Hes1与FIP1L1-PDGFR协同诱导小鼠BMT模型中的AML，并且在5例携带FIP1L1-PDGFR的嗜酸性白血病患者中有2例观察到Hes1过表达。这些结果表明Hes1在抑制髓细胞分化中参与了白血病的发生。

Mutations in a variety of epigenetic factors have been recently identified in various hematological malignancies. We have demonstrated that the mutations in TET2, EZH2 or ASXL1 induce myelodysplastic syndromes (MDS)-like in mouse bone marrow transplant (BMT) model and that derepression of HoxA9 and miR125a induced by ASXL1 mutants via EZH2/PRC2 repression plays critical roles in inducing MDS-like disease.We previously reported that Hes1 plays critical roles in CML-BC. We here demonstrate that MMP9 expression induced by Hes1 via NFkB activation plays some roles in the progression of CML-BC. In addition, we also demonstrated that Hes1 collaborated with FIP1L1-PDGFR in inducing AML in mouse BMT model and that Hes1 overexpression was observed in 2 of 5 patients with eosinophilic leukemia harboring FIP1L1-PDGFR. These results indicate that Hes1 contribute to leukemogenesis in suppressing myeloid differentiation.