Oncogenic Ras in Mouse Models of Leukemia

白血病小鼠模型中的致癌 Ras

• 批准号: 6967226
• 负责人: IRIS T CHAN
• 金额: $ 13.81万
• 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/6967226
• 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(申请人提供)：致癌RAS等位基因是癌症患者中最常见的突变之一，存在于25%-44%的急性髓系白血病(AML)患者中。我们利用Mx1-Cre介导的重组技术，通过内源性启动子在生理水平表达致癌K-ras基因，建立了两种新的致癌K-ras基因介导的造血系统疾病模型。首先，我们建立了单独致癌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K-ras和PML-RARpha转基因协同作用诱发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在白血病发生中的作用，并表明RAS信号通路是AML患者治疗抑制的重要靶点。 这些血液系统疾病的致癌K-ras模型为检验RAS靶向治疗的可行性提供了有价值的临床前平台。进一步的调查将涉及： 具体目的1-使用ras途径抑制剂治疗K-ras诱导的致癌性骨髓增殖性疾病，以确定治疗效果，阐明法尼基转移酶抑制剂的作用机制，并确定对疾病至关重要的下游ras效应通路。 具体目的2-单独使用ras途径抑制剂和中性粒细胞弹性蛋白酶抑制剂治疗由致癌K-ras和PML-RARpha协同作用引起的APL疾病，并与全反式维甲酸(ATRA)联合治疗APL，以测试有前景的新的协同治疗方法。 具体目标3-通过对APL疾病小鼠的造血干细胞和髓系祖细胞纯化群体的详细鉴定，鉴定APL中的白血病干细胞，以及促进细胞自我更新的信号转导途径。