SIGNAL TRANSDUCTION IN HEMATOPOIETIC CELLS MEDIATED BY TYROSINE KINASE FUSIONS

酪氨酸激酶融合介导的造血细胞信号转导

• 批准号: 6346134
• 负责人: D GARY GILLILAND
• 金额: $ 14.86万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6346134
• 关键词: biological signal transduction; bone marrow; cell transformation; chimeric proteins; chronic myelogenous leukemia; growth factor receptors; hematopoiesis; laboratory mouse; molecular cloning; neoplastic cell; neoplastic transformation; oncogenes; platelet derived growth factor; protein structure function; protein tyrosine kinase; tissue /cell culture; transcription factor

An emerging theme in the pathogenesis of human malignancy is the involvement of tyrosine kinases as a consequence of chromosomal translocation. However, the mechanism of transformation of this class of fusion proteins is not well understood, even for the extensively studied BCR-ABL fusion associated with t (9;22) chronic myelogenous leukemia. Our laboratory has recently cloned two new tyrosine kinase fusions, TEL- PDGFRbeta and TEL-ABL, which are associated with t (5;12) and t(9;12) chromosomal translocations respectively, in human leukemias. TEL is a new member of the ETS family of transcription factors, and contributes a highly conserved helix-loop-helix (HLH) domain to both fusions. The objective of this proposal is to determine the mechanism of transformation of TEL- PDGFRbeta and TEL-ABL by analysis of the contribution of the functional domains of TEL, PDGFRbeta and ABL. We hypothesize that transformation is due to aberrant expression and activation of the PDGFRbeta and ABL tyrosine kinases mediated by the TEL HLH domain. Preliminary studies have documented the transforming activity of the fusion proteins, and demonstrate that tyrosine kinase activity of PDGFR and ABL are absolute requirements for transforming activity. The function of the HLH domain in ETS family members is unknown. However, preliminary analysis of these fusions has led us to an interesting discovery: the TEL HLH domain appears to be a protein-protein interaction motif. This finding, in conjunction with the observation that the other TEL allele is deleted in TEL-ABL leukemia and expressed at low levels in TEL-PDGFRbeta leukemia, suggests that TEL loss of function may be important in pathogenesis of leukemia. In Specific Aim 1, we will characterize the signal transduction properties of the TEL-PDGFRbeta fusion protein, and determine which are pivotal in mediating transformation. In Specific Aim 2, we will analyze the signal transduction properties of TEL-ABL, and determine the common themes which unify the transforming properties of TEL-ABL and BCR-ABL. Specific Aim 3 will focus on the role of the TEL HLH domain in transformation and the possibility that loss of function of TEL contributes to pathogenesis of leukemia. Delineation of the mechanism of transformation of TEL-PDGFRbeta TEL-ABL will be facilitated by interactions with each of the members of the Program Project, and may provide insights into therapeutic approaches to human malignancy caused by tyrosine kinase fusions.

人类恶性肿瘤发病机制中的一个新兴主题是 由于染色体异常而涉及酪氨酸激酶 易位。 然而，这一类的转化机制 即使对融合蛋白进行了广泛研究，但人们对融合蛋白的了解还不是很清楚 BCR-ABL 融合与 t (9;22) 慢性粒细胞白血病相关。 我们的 实验室最近克隆了两种新的酪氨酸激酶融合体，TEL- PDGFRbeta 和 TEL-ABL，与 t (5;12) 和 t(9;12) 相关 人类白血病中分别存在染色体易位。 电话是一个新的 ETS 转录因子家族的成员，并贡献了高度 两个融合体都有保守的螺旋-环-螺旋 (HLH) 结构域。 的目标 该提案旨在确定TEL-的转型机制 PDGFRbeta 和 TEL-ABL 通过分析功能的贡献 TEL、PDGFRbeta 和 ABL 结构域。 我们假设转变是 由于 PDGFRbeta 和 ABL 酪氨酸的异常表达和激活 由 TEL HLH 结构域介导的激酶。 初步研究有 记录了融合蛋白的转化活性，并且 证明 PDGFR 和 ABL 的酪氨酸激酶活性是绝对的 转化活动的要求。 HLH结构域的功能 ETS 家族成员未知。 但初步分析这些 融合让我们有了一个有趣的发现：TEL HLH 域出现 成为蛋白质-蛋白质相互作用基序。 这一发现，结合 观察到另一个 TEL 等位基因在 TEL-ABL 中被删除 白血病并在 TEL-PDGFRbeta 白血病中低水平表达，表明 TEL 功能丧失可能在白血病的发病机制中起重要作用。 在 具体目标1，我们将表征信号转导特性 TEL-PDGFRbeta 融合蛋白，并确定哪些是关键的 调解转变。 在具体目标 2 中，我们将分析信号 TEL-ABL 的转导特性，并确定其共同主题 统一了TEL-ABL和BCR-ABL的转换特性。 具体目标 3 将重点关注 TEL HLH 域在转化中的作用以及 TEL 功能丧失可能导致以下疾病的发病机制 白血病。 TEL-PDGFRbeta 转化机制的描述 TEL-ABL 将通过与每个成员的互动来促进 计划项目，并可能提供对治疗方法的见解 由酪氨酸激酶融合引起的人类恶性肿瘤。