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: 6499823
• 负责人: D GARY GILLILAND
• 金额: $ 29.68万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499823
• 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 酪氨酸激酶的参与是染色体 易位 然而，这一类的转化机制 融合蛋白的理解并不充分，即使是广泛研究的 BCR-ABL融合与t（9;22）慢性粒细胞白血病相关 我们 一个实验室最近克隆了两个新的酪氨酸激酶融合，TEL- PDGFR β和TEL-ABL，与t（5;12）和t（9;12）相关 在人类白血病中的染色体易位。 TEL是一个新的 ETS家族转录因子的成员，并有助于高度 保守的螺旋-环-螺旋（HLH）结构域。 的目标 这一建议是为了确定电信转型的机制， PDGFR β和TEL-ABL通过分析功能性 我们假设转化是一种 由于PDGFR β和ABL酪氨酸的异常表达和激活 由TEL HLH结构域介导的激酶。 初步研究已经 记录了融合蛋白的转化活性， 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家庭成员不详。 初步分析，这些 融合使我们有了一个有趣的发现：TEL HLH结构域似乎 是一个蛋白质相互作用基序。 这一发现与 观察到在TEL-ABL中另一个TEL等位基因缺失， 在TEL-PDGFR β白血病中低水平表达，提示 TEL功能缺失可能在白血病发病机制中起重要作用。 在 具体目标1，我们将表征 所述TEL-PDGFR β融合蛋白，并确定哪些在 介导转化。 在具体目标2中，我们将分析信号 转导特性的TEL-ABL，并确定共同的主题， 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结构域在转化中的作用， TEL功能的丧失可能导致 白血病 TEL-PDGFR β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。