Analysis on the molecular mechanisms for the self renewal of the leukemic stem cells and for the leukemcgenesis

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A variety of reciprocal 11q23 translocations generating fusions of MLL(Mixed Lineage Leukemia) with partner genes are frequently found in infant acute leukemia. However, little has been clarified regarding the pathway through which MLL fusion proteins lead to leukemia. We have recently reported the two-step leukemogenesis by MLL fusion proteins in mice models(Ono R, et. al. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J. Clin. Invest 115, 919-929, 2005 ; selected as one of the highlight papers in the April 2005 issue of the Nature Reviews/Cancer). By comparing the effects of two kinds of FLT3 mutants, and constitutively active mutant molecules of Ras, Raf, and STATS, we first identified Ras/Raf/MAPK as synergistic collaborative pathway for MLL fusion proteins to induce acute leukemia. Furthermore, expression of Hoxa9, one of the upregulated molecules in MLL-related human leukemia, and Ras activation were found to recapitulate MLL-fusion-mediated acute leukemia in mice. Hoxa9 is considered to contribute to confer self-renewal activity on leukemic cells, and Ras activation is inferred to induce proliferation of the leukemic cells.Thus this study unveiled the molecular mechanism of MLL-fusion-mediated leukemogenesis, and may help develop the MLL-fusion-targeted therapy in future.