MicroRNA in Acute Myeloid Leukemia

HoxA 9转录因子的功能在人类急性髓性白血病（AML）中具有重要意义 因为HoxA 9的致癌激活是由多个染色体易位诱导的;然而， 独立的研究表明，HoxA 9的表达水平在缺乏这些功能的人AML中具有预后意义。 染色体异常因此，对HoxA 9信号传导的理解将显著影响患者 在AML重要的是，HoxA 9的直接转录靶点以及HoxA 9介导的转录调控机制是研究HoxA 9基因表达的基础。 转型在很大程度上仍然未知。生长因子非依赖性1（Gfi 1）转录抑制因子是 已知诱导粒细胞生成，抑制髓系祖细胞增殖，并在患有 重度先天性中性粒细胞减少症（SCN）。SCN患者患AML的风险增加。我们最近 显示1）Gfi 1抑制HoxA 9、Meis 1和Pbx 1表达，2）Gfi 1和HoxA 9表现出显著的 上位关系，和3）Gfi 1功能丧失是潜在的白血病前期。Gfi 1之间的拮抗作用 而HoxA 9在果蝇中是保守的，我们的初步数据表明，在哺乳动物的骨髓中， 祖细胞集中于microRNA编码基因的表达。我们假设这些 microRNA介导基于Hox的白血病信号传导，特异性microRNA抑制剂可阻断白血病信号传导。 维持基于Hox的白血病起始细胞。拟议的研究将描述功能 microRNA作为基于Hox的白血病癌蛋白的分子信号传导效应物/客户的作用。

The function of the HoxA9 transcription factor is of critical interest in human acute myeloid leukemia (AML) since oncogenic activation of HoxA9 is induced by multiple chromosomal translocations; however, independent studies indicate that the expression level of HoxA9 is prognostic in human AML lacking these chromosomal abnormalities. Thus, an understanding of HoxA9 signaling would significantly impact patients with AML. Importantly, the direct transcriptional targets of HoxA9 and thus mechanism of HoxA9-mediated transformation remain largely unknown. The Growth factor independent-1 (Gfi1) transcriptional repressor is known to induce granulopoiesis, inhibits myeloid progenitor proliferation, and is mutated in patients with severe congenital neutropenia (SCN). SCN patients are at increased risk for AML. We have recently shown that 1) Gfi1 represses HoxA9, Meis1 and Pbx1 expression, 2) Gfi1 and HoxA9 demonstrate dramatic epistatic relationships, and 3) Gfi1 loss of function is potently preleukemic. The antagonism between Gfi1 and HoxA9 is conserved to Drosophila, and our preliminary data indicate that in mammalian myeloid progenitors centers upon the expression of microRNA encoding genes. We hypothesize that these microRNA mediate Hox-based leukemic signaling, and that specific microRNA inhibitors abort the maintenance of Hox-based leukemia initiating cells. The proposed research will delineate the functional role of microRNA as molecular signaling effectors/clients of Hox-based leukemia oncoproteins.