MicroRNA in Acute Myeloid Leukemia

HoxA9转录因子的功能在人类急性髓系白血病(AML)中具有重要意义 由于HoxA9的致癌激活是由多条染色体易位引起的；然而， 独立研究表明，HoxA9的表达水平对缺乏HoxA9的人AML的预后有预测作用 染色体异常。因此，对HoxA9信号的了解将对患者产生重大影响 急性髓系白血病。重要的是，HoxA9的直接转录靶点和HoxA9介导的机制 转型在很大程度上仍是未知的。生长因子非依赖性-1(Gfi1)转录抑制因子是 已知可诱导粒细胞生成，抑制髓系祖细胞增殖，并在慢性粒细胞白血病患者中突变 严重先天性中性粒细胞减少症(SCN)。SCN患者患AML的风险增加。我们最近做了 结果表明：1)Gfi1抑制HoxA9、Meis1和Pbx1的表达；2)Gfi1和HoxA9表现出明显的抑制作用 上位性关系，以及3)Gfi1功能丧失是潜在的白血病前期。Gfi1之间的拮抗作用 而HoxA9在果蝇中是保守的，我们的初步数据表明，在哺乳动物的髓系中 祖细胞以编码基因的microRNA的表达为中心。我们假设这些 MicroRNA介导基于HOX的白血病信号转导，而特定的microRNA抑制剂可终止 基于HOX的白血病启动细胞的维护。拟议的研究将描绘出 微RNA作为HOX白血病癌蛋白分子信号效应/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.