Genetic pathway in molecular pathogenesis of myelodysplastic syndrome (MDS) with AML1 point mutations

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AML1 mutations that have been reported to be frequent in myelodysplastic syndrome (MDS), especially in the therapy-related MDS and AML, are suspected to play a pivotal role for developing MDS/AML. We tried to analyze that radiation or anti-cancer drugs might induce the AML1 mutants in the hematopoietic stem cells. VP16-treated hematopoietic stem cells showed many gene rearrangements in their AML1 and MLL genes after 3 hours recovery, whereas non-VP16-treated cells also showed many of rearrangement bands after 2 weeks culture. These rearrangement bands were not detected in CEBPA gene, suggesting the sensitivity of gene rearrangements to VP16 are various among genes.Although AML1 mutations are suspected to play a pivotal role in the development of MDS/AML, acquisition of additional genetic alterations is also necessary. We suspected that AML1-mutated hematopoietic stem cells might have genetic instability and might easily get partner gene mutations. We performed mouse bone marrow transplantation using bone marrow cells transduced with AML1 mutants. Most mice developed MDS/AML-like symptoms within several months after the transplant. The expression patterns of some genes have been changed by immigration of retrovirus vectors harboring AML1-mutations, and Evil seemed to collaborate with AML1 mutants to develop MDS/AML. We also tried to transduce AML1 mutation into human hematopoietic stem cells, and found their morphological changes and abnormal proliferation. Now we are inducing both AML1 mutant and partner gene mutant into human hematopoietic stem cells. Using this approach, we are able to clarify the molecular pathogenesis of MDS.