Developmental impact of MLL-AF4fusion gene on early hematopoieticstem cells

为了研究MLL-AF4融合基因对早期造血发育的影响，我们构建了MLL-AF4组成表达的小鼠胚胎干细胞（ES）。当通过胚状体（EB）形成检测造血分化时，与对照Ebs相比，含有早期造血干细胞的Tie2^+c-kit^+细胞在表达MLL-AF4的Ebs中显著减少。表达阵列分析表明MLL-AF4作为基因表达的正调控因子上调了多种基因的表达。已知MLL-AF4上调的几个基因在细胞向间充质谱系分化的过程中起重要作用，而造血谱系的转录调节因子则下调。这些表达MLL-AF4的造血前干细胞具有间充质性质，在体外不能引起白血病，表明一些继发性事件是引起白血病的必要条件。MLL-AF4具有影响早期造血细胞分化的潜力，当伴随着一些重要的额外遗传事件时，可能导致白血病转化。

To study the developmental impact of MLL-AF4 fusion gene on early hematopoietic development, mouse embryonic stem (ES) cells with constitutive expression of MLL-AF4 were established. When hematopoietic differentiation was examined by embryoid body (EB) formation, Tie2^+c-kit^+cells which contain early hematopoietic stem cells were significantly reduced in MLL-AF4 expressing Ebs compared to that of control Ebs.Expression array analysis indicated that MLL-AF4 works as positive regulator of gene expression up-regulating various genes. Several genes up-regulated by MLL-AF4 were known to have important roles in cell differentiation to mesenchymal lineage, whereas transcriptional regulator of hematopoietic lineage were down-regulated. These MLL-AF4 expressing pre-hematopoietic stem cells with mesenchymal nature, were unable to cause leukemia in vitroor in vivo, showing that some secondary event is necessary to cause leukemia. MLL-AF4, having the potential to influence early hematopoietic cell differentiation, may cause leukemic transformation whenaccompanied by some important additional genetic events.