DEREGULATION OF MYELOPOIESIS BY ZINC FINGER PROTEIN EVI1

与大多数人类癌症一样，急性髓系白血病(AML)是多种遗传事件的结果，每一种遗传事件都会导致细胞生长控制的一个特定方面的丧失。这种失控的两个关键方面涉及到不受限制的增殖和对分化的阻碍。虽然对后者重要性的间接支持来自于对白血病细胞表型的分析和分化治疗的有效性，但我们还没有明确的分子理解这是如何表现或引起的。Evi-1是一种白血病锌指转录抑制因子，被认为是通过干扰髓系细胞的细胞成熟而发挥作用的。我们已经证明Evi-1可以钝化骨髓生成过程中C/EBPalpha mRNA的积累；C/EBPalpha编码一种转录调控蛋白，对成熟粒细胞的生成是必不可少的。然而，其他髓系必需调节蛋白的转录本不受EVI-1的影响。因此，我们假设EVI-1影响在髓系成熟中起调节作用的一组非常有限的基因的表达。我们进一步假设，EVI-1对这些基因的抑制导致分化受阻。我们将通过鉴定和表征表达EVI-1的髓系祖细胞和对照髓系祖细胞之间的转录差异来实现这一点。差异表达的基因可能是已知的或新的，也可能是EVI-1作用的直接或间接靶点。此外，我们建议通过评估表达Evi-1的细胞和对照细胞超越Evi-1诱导的对骨髓生成的干扰的能力来测试这些转录差异的重要性。

As is the case with most human cancers, acute myeloid leukemia (AML) is the result of multiple genetic events, each of which leads to loss of a particular aspect of cellular growth control. Two key aspects of this loss of control involve unrestrained proliferation and a block to differentiation. While circumstantial support for the importance of the latter has come from the analysis of leukemic cell phenotype and the efficacy of differentiation therapy, we do not as yet have a clear molecular understanding of how this is manifested or caused. Evi-1 is a leukemogenic zinc finger transcriptional repressor that is thought to act by interfering with cellular maturation of myeloid cells. We have shown that Evi-1 can blunt the accumulation of C/ebpalpha mRNA during myelopoiesis; C/ebpalpha encodes a transcriptional regulatory protein that is essential for the generation of mature granulocytes. However, transcripts of other myeloid-essential regulatory proteins are unaffected by Evi-1. We therefore hypothesize that EVI-1 affects the expression of a very limited subset of genes that play a regulatory role in myeloid maturation. We further hypothesize that the repression of these genes by EVI-1 results in the block to differentiation. We will approach this by identifying and characterizing differences in transcription between Evi-1-expressing myeloid progenitor cells and control myeloid progenitor cells. The differentially expressed genes may be known or novel, and may be direct or indirect targets of Evi-1 action. Furthermore, we propose to test the importance of these transcriptional differences between Evi-1 expressing cells and control cells by assessing their ability to override the Evi-1 induced interference with myelopoiesis.