Toward the comprehensive understanding of molecular mechanisms of hematopoietic malignancies

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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.