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（由申请人提供）：致癌性RAS等位基因是癌症患者中最常检测到的突变之一，并且有25-44％的急性髓样白血病（AML）的突变。我们通过使用MX1-CRE介导的重组从其内源性启动子中从其内源性启动子中表达了致癌性K-RAS在生理启动子处的致癌K-RAS在生理水平上的表达，从而产生了两个新型的致癌性K-RAS介导的造血性疾病。首先，我们建立了仅致癌K-RAS引起的骨髓增生性疾病（MPD）模型。其次，我们建立了由致癌性K-RAS和PML-Raralpha Transgene的合作作用引起的急性临床白血病（APL）模型。这些小鼠模型验证了致癌性RAS对白血病发生的贡献，并将RAS信号通路视为AML患者治疗抑制的重要靶标。 这些造血疾病的致癌K-RAS模型代表了测试靶向RAS靶向治疗的可行性的宝贵临床前平台。进一步的调查将涉及： 具体目的1-在致癌性K -RAS上使用RAS途径抑制剂诱导脊髓增生性疾病来确定治疗疗效，阐明了Farneylysylansferase抑制剂的作用机制，并确定下游RAS RAS效应对疾病的关键途径。 特定目标2-仅由Oncenic K-Ras和PML Raralpha与RAS途径抑制剂和中性粒细胞弹性酶抑制剂的合作作用以及所有反式视黄酸（ATRA）结合以测试APL的有希望的新疗法治疗的APL疾病。 特定的目标3-通过APL鉴定了APL中白血病干细胞的鉴定，以及通过详细表征造血干细胞的纯化群体和来自APL患病小鼠的骨质祖细胞的纯化群体来促进细胞自我更新的信号转导途径。