analysis of leukemogenesis by the expression of EVI1/MEL1S, the PR domain-defective proteins, in EVI1/MEL1 gene family

EVI1和MDS1/EVI1样基因1(MEL1)是髓系白血病发病机制中的转录调控因子。然而，它们转录功能的分子基础仍然难以捉摸。最近，我们通过对缺乏EVI1的小鼠的分析，发现EVI1在体外和体内都直接调节GATA-2的表达，并在造血干细胞的增殖和分化中发挥重要作用。在这里，我们发现EVI1与其位于GATA-2上游约6-7kb的DNA共有序列是外显子，并上调了EML-C1中GATA-2基因的表达。EVI1是小鼠多能祖细胞系HEL，是人红白血病细胞系。同样，EVI1与GATA-2基因在小鼠NSF58和M1S2，人AML1和Kasumi-3，MOLM1，EVI1过表达的白血病细胞系中的表达有关。但在依赖IL-3的小鼠髓系细胞系L-G3中，与EVI1一样，PR结构域缺陷短型MEL1S的过表达阻断了G-CSF诱导的髓系分化，下调了GATA-2基因的表达。这些发现突出了EVI1/MEL1S调控的GATA-2基因的表达与EVI1/MEL1S和组蛋白乙酰转移酶/HDAC相互作用的关系，以及这些因素如何影响EVI1/MEL1S的基因表达和白血病发生。

The ecotropic viral integration site-1 (EVI1) and MDS1/EVI1-like gene 1 (MEL1) were identified as transcriptional regulators that were the causative factors in pathogenesis of myeloid leukemia. However, the molecular basis of their transcriptional functions has remained elusive. Recently, we have shown that EVI1 directly regulates the expression of GATA-2 both in vitro and in vivo and plays an important role in proliferation and differentiation of the hematopoietic stem cell by the analysis of mice lacking EVI1. Here, we show that EVI1 binds to its DNA consensus sequence located around 6-7 kb upstream region of the GATA-2 IS exon and up-regulates the expression of GATA-2 gene in EML-C1, a murine multipotent progenitor cell line, HEL, a human erythroleukemia cell line. Similarly, EVI1 was related to the expression of GATA-2 gene in mouse NSF58 and M1S2, human AML1 and Kasumi-3, MOLM1, EVI1-overexpressing leukemia cell lines. But Overexpression of MEL1S, PR domain-defective short form, as same as EVI1, in L-G3, a IL-3-dependent murine myeloid cell line, blocks G-CSF-induced myeloid differentiation and down-regulate the expression of GATA-2 gene. These findings highlight the relationship between the expression of GATA-2 gene regulated by EVI1/MEL1S and the interaction of EVI1/MEL1S and histone acetyltransferases/HDAC and how these factors affect the gene expression and leukemogenesis of EVI1/MEL1S in leukemia cells.