急性白血病基因MLL编码一个组蛋白甲基化转移酶，能通过表观遗传机制调控Hox等基因的表达。它与70多种基因发生重排是导致急性淋巴细胞白血病（ALL）和急性骨髓性白血病（AML）发生的主要原因。由于小鼠mll基因敲除导致早期胚胎死亡，因此对于它在早期胚胎发育中的作用及其分子机制仍很不清楚。
中国科学院水生生物研究所肖武汉实验室的博士生万小洋等，利用Morpholino介导的基因敲降技术，系统分析了mll在斑马鱼早期胚胎发育过程中的作用。他们发现，mll对于斑马鱼胚胎血细胞的发生是必需的。它的敲降使斑马鱼血细胞的发生严重受阻，并最终导致胚胎死亡，与斑马鱼血细胞发生相关的标记基因的表达都受到严重影响。此外，他们还发现，与在哺乳动物中发现的一样，mll基因敲降也严重影响斑马鱼hox基因的表达，但是hox基因的过表达并不能拯救mll敲降的表型，这说明在介导血细胞的发生过程中，除hox基因外，还有其他基因同样受到mll的调控。
他们进一步通过基因芯片技术，筛选到一个受mll抑制的重要靶基因——Gadd45αa。Gadd45αa的过表达能够模拟mll敲降后的表型，而Gadd45αa的敲降能够部分拯救血细胞标记基因的表达，因此，该研究表明mll可能通过调控Gadd45αa的表达，从而影响血细胞的发生。
目前该研究结果已于7月22日在线发表于Journal of Biological Chemistry上，该研究工作得到科技部"973"、国家自然科学基金和中国科学院项目的资助。
生物探索推荐英文摘要：
Zebrafish mll is essential for haematopoiesis
Abstract
Studies implicate an important role for the mixed lineage leukemia (Mll) gene in haematopoiesis, mainly through maintaining Hox gene expression. However, the mechanisms underlying Mll-mediated haematopoiesis during embryogenesis remain largely unclear. Here, we investigate the role of mll during zebrafish embryogenesis, in particular, haematopoiesis. Mll depletion caused severe defects in haematopoiesis as indicated by a lack of blood flow and mature blood cells as well as a significant reduction in expression of hematopoietic progenitor and mature blood cell markers. Furthermore, mll depletion prevented the differentiation of hematopoietic progenitors. In addition, we identified the N-terminal mini-peptide of Mll acted as a dominant negative form to disrupt normal function of mll during embryogenesis. As expected, mll knockdown altered the expression of a subset of hox genes. However, overexpression of these down-regulated hox genes only partially rescued the blood deficiency, suggesting that mll may target additional genes to regulate haematopoiesis. In the mll morphants, microarray analysis revealed a dramatic up-regulation of gadd45αa. Multiple assays indicate that mll inhibited gadd45αa expression and that overexpression of gadd45αa mRNA led to a phenotype similar to the one seen in the mll morphants. Taken together, these findings demonstrate that zebrafish mll plays essential roles in haematopoiesis and that gadd45αa may serve as a potential down-stream target for mediating mll function in haematopoiesis.
