MicroRNA in Acute Myeloid Leukemia

急性髓系白血病中的 MicroRNA

基本信息

批准号：
8852567
负责人：
H. LEIGHTON GRIMES
金额：
$ 31.75万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8852567
关键词：
11q23 Accounting Acute Myelocytic Leukemia Affect Aftercare Age Biological Bone Marrow Cells Cells Cellular biology Cessation of life Chromosomal translocation Chromosome abnormality Client Clinical Colony-forming units Complex Data Dissection Drosophila genus Genes Granulopoiesis Growth Factor Hand Hematopoiesis Hematopoietic Hematopoietic Neoplasms Human MLL-AF9 Maintenance Malignant Neoplasms Mediating MicroRNAs Modeling Molecular Mus Mutate Myelogenous Myeloid Leukemia Neutropenia Oncogene Proteins Oncogenes Oncogenic Outcome Patients Population Publications Publishing Reagent Relapse Relative (related person)Research Resistance Risk Role Signal Transduction Splenocyte Therapeutic Toxic effect Transcription Repressor/Corepressor Transplantation Tumor Suppressor Proteins United States Work base cell transformation chemical genetics chemotherapy defined contribution design gene repression in vivo inhibitor/antagonist interest leukemia leukemia treatment leukemogenesis loss of function mouse model novel novel strategies pre-clinical progenitor prognostic research study transcription factor tumorigenesis validation studies

项目摘要

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.

HoxA9 转录因子的功能在人类急性髓系白血病 (AML) 中至关重要因为 HoxA9 的致癌激活是由多重染色体易位诱导的；然而，独立研究表明，HoxA9 的表达水平在缺乏这些的人类 AML 中具有预后意义染色体异常。因此，了解 HoxA9 信号传导将对患者产生重大影响与反洗钱。重要的是，HoxA9 的直接转录靶标以及 HoxA9 介导的机制转型在很大程度上仍然未知。生长因子独立 1 (Gfi1) 转录抑制因子是已知可诱导粒细胞生成，抑制骨髓祖细胞增殖，并在患有以下疾病的患者中发生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。我们最近有显示 1) Gfi1 抑制 HoxA9、Meis1 和 Pbx1 表达，2) Gfi1 和 HoxA9 表现出戏剧性的作用上位关系，3) Gfi1 功能丧失可能导致白血病前期。 Gfi1之间的拮抗作用 HoxA9 在果蝇中是保守的，我们的初步数据表明在哺乳动物骨髓中祖细胞以 microRNA 编码基因的表达为中心。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 抑制剂会中止维持基于 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器/客户的作用。