MicroRNA in Acute Myeloid Leukemia

描述（由申请人提供）：HoxA9转录因子的功能对人类急性髓性白血病（AML）至关重要，因为HoxA9的致癌激活是由多染色体易位诱导的；然而，独立研究表明，HoxA9的表达水平在缺乏这些染色体异常的人类AML中具有预后作用。因此，了解HoxA9信号将显著影响AML患者。重要的是，HoxA9的直接转录靶点以及HoxA9介导的转化机制在很大程度上仍然未知。已知生长因子独立-1 （Gfi1）转录抑制因子可诱导粒细胞生成，抑制髓系祖细胞增殖，并在严重先天性中性粒细胞减少症（SCN）患者中发生突变。SCN患者患AML的风险增加。我们最近发现，1)Gfi1抑制HoxA9、Meis1和Pbx1的表达，2)Gfi1和HoxA9表现出显著的上位性关系，3)Gfi1功能丧失可能是白血病前期。Gfi1和HoxA9之间的拮抗作用仅在果蝇中存在，我们的初步数据表明，在哺乳动物髓系祖细胞中，这种拮抗作用主要集中在microRNA编码基因的表达上。我们假设这些microRNA介导基于hox的白血病信号传导，并且特定的microRNA抑制剂中止了基于hox的白血病起始细胞的维持。拟议的研究将描述microRNA作为基于hox的白血病癌蛋白的分子信号效应器/客户的功能作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Acute myeloid leukemia, a cancer of the blood, accounts for 1.2% of cancer deaths in the United States; however, rates are expected to increase as the population ages and successful therapeutics are expected to benefit patients with leukemia and abnormal hematopoiesis. The proposed work may be considered both an examination of oncogenic signaling, and a pre-clinical proof of principle for the use of microRNA inhibitors in the treatment of leukemia. microRNA antagonists are being developed for clinical use by several companies and the proposed experiments are anticipated to be pioneering work to move the concept forward.