Toward the comprehensive understanding of molecular mechanisms of hematopoietic malignancies

我们主要利用小鼠骨髓移植(BMT)模型对白血病、骨髓增生异常综合征(MDS)和骨髓增生性肿瘤(MPN)的发病机制进行了研究。涉及白血病发生的突变主要分为两大类：I类突变诱导增殖或阻断细胞凋亡，而II类突变阻碍造血细胞分化。在本研究项目中，我们使用小鼠骨髓移植模型显示，I类突变可诱发MPN，II类突变可诱发MDS，I类和II类突变组合可诱发急性白血病。我们还指出，额外的I类突变，如Flt3-ITD或Evi1的过表达可能导致MDS进展为显性白血病，而额外的I类突变，如Hes1的过表达，可能导致MPN进展为急性白血病，CML的急变。因此，突变的组合和每个突变的时间将决定MDS/显性白血病、MPN/显性白血病和急性白血病的病程。

We studied the molecular mechanisms of etiology of leukemia, myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) mainly through the usage of mouse bone marrow transplant (BMT) model. Mutations involved in leukemogenesis are classified into two major groups : class I mutations induced proliferation or block apoptosis while class II mutations hamper differentiation of hemopoietic cells. In this research project, we have shown using a mouse BMT model that class I mutations induce MPN, that class II mutations induce MDS and that combination of class I and class II mutations induce acute leukemia. We have also indicated that additional class I mutations such as FLT3-ITD or overexpression of Evi1 could lead to progression of MDS to overt leukemia and that additional class mutations such as overexpression of Hes1 could result in progression of MPN to acute leukemia, blast crisis of CML. Thus, the combinations of mutations and the timing of each mutation will determine the disease course of MDS/overt leukemia, MPN/overt leukemia and acute leukemia.