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

在婴儿急性白血病中经常发现各种相互的11q23易位，产生MLL（混合谱系白血病）与伴侣基因的融合。然而，关于MLL融合蛋白导致白血病的途径尚不清楚。我们最近报道了MLL融合蛋白在小鼠模型中的两步白血病发生（Ono R，等）。MLL融合蛋白的二聚化和FLT3激活协同诱导多谱系白血病发生。j .中国。《投资管理》（英文版），2005；入选《自然评论/癌症》2005年4月刊的重点论文之一。通过比较两种FLT3突变体以及Ras、Raf和STATS组成型活性突变分子的作用，我们首次发现Ras/Raf/MAPK是MLL融合蛋白诱导急性白血病的协同通路。此外，在mll相关的人类白血病中上调的分子之一Hoxa9的表达和Ras的激活被发现概括了小鼠mll融合介导的急性白血病。Hoxa9被认为有助于赋予白血病细胞自我更新活性，Ras激活被推断为诱导白血病细胞增殖。因此，本研究揭示了mll融合介导的白血病发生的分子机制，可能有助于未来mll融合靶向治疗的发展。

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.