Oncogenic Ras in Mouse Models of Leukemia
白血病小鼠模型中的致癌 Ras
基本信息
- 批准号:7097343
- 负责人:
- 金额:$ 13.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:acute myelogenous leukemiaalkyltransferaseall trans retinolantineoplasticsbiological signal transductionelastase inhibitorenzyme activityenzyme inhibitorsgene expressiongene mutationgene targetinggenetically modified animalshematopoietic stem cellsleukemiamicroarray technologymyeloproliferative neoplasmneoplasm /cancer geneticsneoplastic growthoncogenesproteomicswestern blottings
项目摘要
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,并且存在于 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,通过小鼠造血系统中的内源性启动子在生理水平上表达致癌 K-ras,生成了两种致癌 K-ras 介导的造血疾病的新模型。首先,我们建立了仅由致癌 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-RARalpha 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,并表明 RAS 信号通路是 AML 患者治疗抑制的重要靶点。
这些造血系统致癌 K-ras 模型代表了测试 RAS 靶向治疗可行性的宝贵临床前平台。进一步的调查将涉及:
具体目标 1 - 使用 ras 通路抑制剂治疗致癌 K-ras 诱导的骨髓增生性疾病,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。
具体目标 2 - 单独使用 ras 通路抑制剂和中性粒细胞弹性蛋白酶抑制剂,以及与全反式维甲酸 (ATRA) 联合治疗由致癌 K-ras 和 PML-RARα 协同作用引起的 APL 疾病,以测试有希望的新协同疗法对于 APL。
具体目标 3 - 通过对患有 APL 的患病小鼠的纯化造血干细胞和骨髓祖细胞群进行详细表征,鉴定 APL 中的白血病干细胞,以及参与促进细胞自我更新的信号转导途径。
项目成果
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