c-Abl and PKC-eta in Cell Development and Leukemia

c-Abl 和 PKC-eta 在细胞发育和白血病中的作用

• 批准号: 7056186
• 负责人: Mark S. Schlissel
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056186
• 关键词: B cell receptor; B lymphocyte; apoptosis; biological signal transduction; cell cycle; cell differentiation; cell transformation; flow cytometry; genetically modified animals; laboratory mouse; leukemia; microarray technology; protein kinase C; protein tyrosine kinase; protooncogene; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Developing B cells undergo regulated cell division and apoptosis in response to their success in assembling the genes encoding their antigen receptors. In addition, the specificity of these receptors is monitored and developing cells with the potential for self-specificity are signaled to either edit their receptors or undergo apoptosis. This research proposal focuses on a protein tyrosine kinase, c-Abl, which our preliminary data and the experiments of others lead us to believe may be involved in these key developmental processes, c-Abl is the cellular homologue of v-Abl, the transforming gene of the Abelson Murine Leukemia Virus (A-MuLV) which causes acute B cell leukemia in mice. In humans, c-Abl is involved in a disease-associated chromosomal translocation which generates the BCR-Abl fusion protein in several forms of leukemia. We propose to test hypotheses regarding the biological functions of the Abl kinase in developing B cells and its role in transformation through pursuit of two specific aims. First, we will perform experiments aimed at understanding how v-Abl disrupts signaling pathways, blocks differentiation, and prevents the apoptosis of leukemic murine pro-B cell lines. These experiments will use a newly available specific inhibitor of the Abl tyrosine kinase, STI-571 (Gleevec), DNA microarrays, and a recently-developed retroviral cDNA cloning strategy called CPR. Second, we will test hypotheses regarding the role of c-Abl in the regulation of cell proliferation, viability, gene expression, pre-BCR signaling, allelic exclusion, receptor editing and clonal deletion during normal murine B cell development. We will attempt to identify the critical targets of the Abl kinase involved in these processes. These experiments will take advantage of primary cell culture systems and STI-571, as well as available null mutations in ARG (Abl-related gene) and c-Abl. These studies are significant because of the involvement of c-Abl in the etiology of chronic myelogenous leukemia and acute lymphocytic leukemia in humans and the growing use of the Abl inhibitor STI-571 in the clinical treatment of various malignancies.

描述（由申请人提供）：开发B细胞会因其在组装编码其抗原受体的基因方面的成功而受到调节的细胞分裂和凋亡。此外，对这些受体的特异性进行监测，并发出具有自我特异性的发育细胞，以编辑其受体或凋亡。这项研究的提案侧重于蛋白质酪氨酸激酶C-ABL，我们的初步数据和其他人的实验使我们相信可能参与了这些关键的发育过程，C-ABL是V-ABL的细胞同源物，V-ABL是Abelson Murine Leukemia病毒（A-Mulv）的转化基因，从而导致尖锐的尖锐的尖锐的尖锐的Leukemia。在人类中，C-ABL参与了与疾病相关的染色体易位，该染色体易位以几种形式的白血病产生BCR-ABL融合蛋白。我们建议通过追求两个特定目标来检验有关ABL激酶在开发B细胞中的生物学功能及其在转化中的作用的假设。首先，我们将进行旨在了解V-ABL如何破坏信号通路，阻止分化并防止白血病鼠Pro-B细胞系的凋亡的实验。这些实验将使用ABL酪氨酸激酶，STI-571（Gleevec），DNA微阵列和最近开发的逆转录病毒cDNA克隆策略的新近可用的特异性抑制剂。其次，我们将检验有关c-ABL在正常鼠B细胞发育过程中C-ABL在调节细胞增殖，生存力，基因表达，前BCR信号，受体编辑和克隆缺失中的作用中的作用的假设。我们将尝试确定这些过程中涉及的ABL激酶的关键靶标。这些实验将利用原代细胞培养系统和STI-571，以及ARG（ABL相关基因）和C-ABL中的无效突变。这些研究之所以重要，是因为C-ABL参与了慢性粒细胞性白血病和急性淋巴细胞性白血病的病因，以及对ABL抑制剂STI-571在各种恶性肿瘤的临床治疗中的日益增长的使用。