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

最近在各种恶性血液病中发现了多种表观遗传因子的突变。我们已经证明TET 2、EZH 2或ASXL 1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）样疾病，ASXL 1突变通过EZH 2/PRC 2抑制诱导HoxA 9和miR 125 a去抑制在诱导MDS样疾病中起关键作用。我们在这里证明，MMP 9的表达诱导Hes 1通过NF κ B活化在CML-BC的进展中发挥了一定的作用。此外，我们还证明了Hes 1与FIP 1 L1-PDGFR在小鼠BMT模型中协同诱导AML，并且在5例携带FIP 1 L1-PDGFR的嗜酸性粒细胞白血病患者中观察到2例Hes 1过表达。这些结果表明，Hes 1有助于抑制髓样分化的白血病发生。

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.