Oncogenic Ras in Mouse Models of Leukemia

白血病小鼠模型中的致癌 Ras

• 批准号: 7097343
• 负责人: IRIS T CHAN
• 金额: $ 13.85万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-20 至 2006-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097343
• 关键词: acute myelogenous leukemia; alkyltransferase; all trans retinol; antineoplastics; biological signal transduction; elastase inhibitor; enzyme activity; enzyme inhibitors; gene expression; gene mutation; gene targeting; genetically modified animals; hematopoietic stem cells; leukemia; microarray technology; myeloproliferative neoplasm; neoplasm /cancer genetics; neoplastic growth; oncogenes; proteomics; western blottings

DESCRIPTION (provided by applicant): Oncogenic RAS alleles are among the most frequently detected mutations in patients with cancer, and are present in 25-44% of patients with acute myeloid leukemia (AML). We generated two novel models of oncogenic K-ras mediated hematopoietic disease through expression of oncogenic K-ras at physiologic levels from its endogenous promoter in the murine hematopoietic system using Mx1-Cre-mediated recombination. First, we established a model of myeloproliferative disease (MPD) induced by oncogenic K-ras alone. Second, we established a model of acute promyelocytic leukemia (APL) induced by the cooperative effects of oncogenic K-ras and a PML-RARalpha transgene. These mouse models validate the contribution of oncogenic RAS to leukemogenesis and implicate the RAS signaling pathway as an important target for therapeutic inhibition in patients with AML. These oncogenic K-ras models of hematopoietic disease represent valuable preclinical platforms to test the feasibility of RAS-targeted therapy. Further investigations will involve: Specific Aim 1 - Use of ras pathway inhibitors on the oncogenic K-ras induced myeloproliferative disease to ascertain therapeutic efficacy, elucidate the mechanism of action of farnesyltransferase inhibitors, and determine the downstream ras effector pathways critical for disease. Specific Aim 2 - Treatment of the APL disease induced by the cooperative effects of oncogenic K-ras and PML-RARalpha with ras pathway inhibitors and neutrophil elastase inhibitors alone, and in combination with all trans retinoic acid (ATRA) to test promising new synergistic therapies for APL. Specific Aim 3 - Identification of the leukemic stem cell in APL, and the signal transduction pathways involved in promoting cellular self-renewal through detailed characterization of purified populations of hematopoietic stem cells and myeloid progenitors from diseased mice with APL.

描述（由申请人提供）：致癌RAS等位基因是癌症患者中最常检测到的突变之一，在25-44%的急性髓性白血病（AML）患者中存在。我们通过mx1 - cre介导的重组，在小鼠造血系统中通过其内源性启动子在生理水平上表达致癌K-ras介导的两种新的致癌K-ras介导的造血疾病模型。首先，我们建立了单纯由致癌基因K-ras诱导的骨髓增生性疾病（MPD）模型。其次，我们建立了由致癌性K-ras和pml - rarα转基因协同作用诱导的急性早幼粒细胞白血病（APL）模型。这些小鼠模型验证了致癌RAS对白血病发生的贡献，并暗示RAS信号通路是AML患者治疗抑制的重要靶点。