MOLECULAR SENSITIZATION OF P210BCR-ABL POSTIVIE CELLS TO THERAPY--CML

P210BCR-ABL阳性细胞对治疗的分子增敏--CML

• 批准号: 6102546
• 负责人: ALBERT B DEISSEROTH
• 金额: --
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6102546
• 关键词: apoptosis; bone marrow purging; cell cycle; cell line; cell proliferation; cell transplantation; chimeric proteins; chronic myelogenous leukemia; combination cancer therapy; drug resistance; genetic transduction; hematopoietic stem cells; human tissue; interferon alpha; laboratory mouse; molecular oncology; neoplasm /cancer chemotherapy; neoplastic transformation; oncoproteins; phosphorylation; protein kinase; protein tyrosine kinase; protooncogene; synthetic peptide; tumor suppressor proteins

The P145 product of the cellular A belson (c-abl) gene has been shown to mediate inhibition of cell cycle progression and apoptosis at the Gl/S interface when over-expressed in cells or when cells are exposed to genotoxic stress as radiation therapy and chemotherapy. In contrast, the presence of the abnormal counterpart of P145c-abl, the P210crabl, is associated with the phenotypes of growth factor independent growth, anchorage independent growth, apoptosis rescue and genetic instability in chronic myelogenous leukemia (CML). In order to study the interaction of these two proteins which have structural similarities in the abl domain, but have such opposing effects in the myeloid cells, and to identify the key substrates of bcrabl and c-abl proteins, we have modified a myelogenous leukemia cell line so that the expression of the P210crabl protein is regulated by the extracellular concentration of tetracycline. We have shown that the ration of the P210crabl/p145c-abl proteins, and the growth of these cells, in the absence of IL3, is dependent on the tetracycline concentration. We will use this cell line to test if bcrabl proteins interact with the Stress Activated Protein Kinase (SAP) pathway as does the c-abl, if the substrates or sites of phosphorylation of the c- abl or bcrabl proteins are the same or different, and which substrates or sites of modifications or substrates are associated with the emergence of P210crabl transformation. Since c-abl is known to promote apoptosis in response to genotoxic stress, and the bcrabl is known to rescue from apoptosis, we are proposing to use this cell line to also study if the sensitivity to chemotherapy and interferon therapy is different as the ratio of P210 bcrabl/P145c-abl changes. We will use peptide transcription units which selective interrupt the interaction of P210 bcrabl with it substrates without affecting the P145c-abl kinase to discriminate between effects of P210 bcrabl and P145c-abl, and to reverse the transformed phenotype of the CML cell. We will use the information generated by these studies to design new approaches to the therapy of CML, including the design and testing of peptidomimetic compounds for the inhibition of P210 bcrabl action in P210 bcrabl positive cells.

细胞A Belson（C-ABL）基因的P145产物已显示为 调解对细胞周期进程和凋亡的抑制作用 当细胞过度表达或将细胞暴露于细胞中时接口 遗传毒性应激作为放射治疗和化学疗法。相反， P145C-ABL（P210CRABL）的异常对应物为 与生长因子独立生长的表型相关， 锚定独立生长，凋亡救援和遗传不稳定性 慢性骨髓性白血病（CML）。为了研究 这两种蛋白质在ABL结构域中具有结构相似性， 但是在髓样细胞中具有这种相反的作用，并确定 BCRABL和C-ABL蛋白的关键底物，我们修改了A 脊髓性白血病细胞系，因此P210Crabl的表达 蛋白质受四环素的细胞外浓度调节。 我们已经证明了p210crabl/p145c-abl蛋白的评分，以及 在没有IL3的情况下，这些细胞的生长取决于 四环素浓度。我们将使用此细胞系来测试是否bcrabl 蛋白质与应激活化蛋白激酶（SAP）途径相互作用 与C-ABL一样，如果C-的底物或磷酸化位点 ABL或BCRABL蛋白是相同或不同的，哪些底物或 修改或底物的位点与出现有关 P210Crabl转换。由于已知C-ABL促进凋亡 对遗传毒性应激的反应，并且已知Bcrabl可以从 凋亡，我们建议使用该细胞系来研究 对化学疗法和干扰素治疗的敏感性与 p210 bcrabl/p145c-abl的比率变化。我们将使用肽转录 选择性中断p210 bcrabl与它的相互作用的单位 底物不影响P145C-ABL激酶以区分 p210 bcrabl和p145c-abl的影响，并逆转转化 CML细胞的表型。我们将使用这些生成的信息 设计用于CML治疗的新方法的研究，包括 抑制p210的肽瘤化合物的设计和测试 BCRABL作用在P210 BCRABL阳性细胞中。