TREATMENT OF BCR/ABL CAUSED LEUKEMIAS WITH FTIs

使用 FTI 治疗 BCR/ABL 引起的白血病

• 批准号: 6732623
• 负责人: Nora C Heisterkamp
• 金额: $ 24.79万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732623
• 关键词: alkyltransferase; apoptosis; cell adhesion; chromosome translocation; cytokine; enzyme activity; enzyme inhibitors; genetically modified animals; guanine nucleotide binding protein; guanosinetriphosphatases; laboratory mouse; leukemia; mitogens; neoplasm /cancer chemotherapy; neoplastic process; nonhuman therapy evaluation; phosphomonoesterases; protein tyrosine kinase

DESCRIPTION: The Bcr/Abl oncoprotein causes the development of Ph-chromosome-positive leukemias. Bcr/Abl P210 and P190 share a domain of Abi which encodes a deregulated tyrosine kinase. This activity perturbs a number of downstream signal transduction pathways including that of the small GTPase Ras. Inhibitors of the enzyme farnesyltransferase (FTIs) have been tested as possible therapeutic agents against Ras-associated solid tumors in man. We have generated a transgenic mouse model which clinically mimics Ph-positive acute lymphoblastic leukemia and tested the potential therapeutic properties of an FTI in this model. Our data show that FTIs are surprisingly potent in preventing the emergence of overt leukemia in our mice. We therefore hypothesize that Ffls are effective in the treatment of Bcr/AbI caused leukemias by interfering with specific small CTPases necessary for disease progression. We will explore this by determining which cellular characteristics known to be altered by Bcr/AbI expression including apoptosis, cytokine independence, mitogenesis and adhesion are affected by the FTIs in BaF3 lymphoid cells with regulatable Bcr/Abl expression. It will also be investigated which small GTPases including Ras are activated by Bcr/Abl in cell line and animal models, and which are targeted by treatment with the FTIs. In addition, we will evaluate whether the FTls are effective against terminal-stage disease in the Bcr/AbI P190 transgenic mouse model, whether they can cure P190-caused leukemia/lymphoma in a bone marrow transplant model and whether Bcr/Abl-expressing cells develop resistance to FTIs. By utilizing a compound which apparently acts on downstream targets of Bcr/Abl in vivo, these experiments will provide unique insights into the mechanisms by which Bcr/AbI causes leukemia. These studies will also help pinpoint which pathway(s) are critical in transducing the oncogenic signals of Bcr/Abl, which could provide additional targets for therapeutic intervention. Finally, data will emerge which will be invaluable in the assessment nf Using FTIs in the treatment nf Ph-positive leukemia in man

描述：Bcr/Abl癌蛋白导致 Ph染色体阳性白血病Bcr/Abl P210和P190共享Abi结构域 其编码去调节的酪氨酸激酶。这一活动扰乱了一些 下游信号转导途径，包括小GT3 Ras。 法尼基转移酶（FTIs）的抑制剂已经被测试为 可能的治疗药物对Ras相关的实体瘤的人。我们有 产生了临床上模拟Ph阳性急性 淋巴母细胞白血病，并测试了潜在的治疗特性， 在这个模型中，我们的数据显示，FTI在以下方面具有惊人的效力： 防止小鼠出现明显的白血病。因此我们 假设FFL在治疗Bcr/AbI引起的 通过干扰疾病所必需的特异性小CTPases来治疗白血病 进展我们将通过确定哪些细胞特征 已知通过Bcr/AbI表达改变，包括细胞凋亡、细胞因子 BaF 3中的FTI影响细胞的独立性、有丝分裂和粘附 Bcr/Abl表达可调控的淋巴样细胞。还将 研究了Bcr/Abl在细胞中激活哪些小GTP酶，包括Ras 线和动物模型，并且其通过用FTI治疗而被靶向。在 此外，我们亦会评估FTLS是否能有效地 在Bcr/AbI P190转基因小鼠模型中， 可在骨髓移植模型中治愈P190引起的白血病/淋巴瘤， 表达Bcr/Bcl-2的细胞是否对FTIs产生耐药性。通过利用 在体内明显作用于Bcr/Abl下游靶点的化合物，这些 实验将提供独特的见解Bcr/AbI的机制， 会导致白血病这些研究还将有助于查明哪些途径是 在Bcr/Abl的致癌信号转导中起关键作用， 治疗干预的其他目标。最后，数据将出现 这在评估中将是非常宝贵的，在治疗中使用FTI， 人Ph阳性白血病