DEREGULATION OF MYELOPOIESIS BY ZINC FINGER PROTEIN EVI1

与大多数人类癌症一样，急性髓细胞白血病（AML）是多种遗传事件的结果，每种遗传事件都导致细胞生长控制的特定方面丧失。这种失控的两个关键方面涉及不受限制的增殖和对分化的阻断。 虽然间接支持的重要性，后者来自白血病细胞表型和分化治疗的疗效分析，我们还没有一个明确的分子理解，这是如何表现或引起的。 Evi-1是一种致白血病的锌指转录抑制因子，被认为通过干扰骨髓细胞的细胞成熟而起作用。 我们已经表明，Evi-1可以钝化C/ebpalpha mRNA的积累，在骨髓细胞; C/ebpalpha编码的转录调控蛋白，这是必不可少的成熟粒细胞的生成。 然而，其他骨髓必需调节蛋白的转录物不受Evi-1的影响。因此，我们假设EVI-1影响在骨髓成熟中起调节作用的非常有限的基因子集的表达。 我们进一步假设，这些基因的抑制EVI-1的结果在块分化。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解决这一问题。 差异表达的基因可以是已知的或新的，并且可以是Evi-1作用的直接或间接靶标。 此外，我们建议测试Evi-1表达细胞和对照细胞之间的这些转录差异的重要性，通过评估它们的能力，推翻Evi-1诱导的干扰骨髓生成。

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.