SIGNAL TRANSDUCTION IN HEMATOPOIETIC CELLS MEDIATED BY TYROSINE KINASE FUSIONS

人类恶性肿瘤发病机制中的一个新兴主题是 染色体导致的酪氨酸激酶的参与 易位。然而，这一类人的转化机制 融合蛋白还不是很清楚，即使是对那些被广泛研究的 Bcr-abl融合与t(9；22)慢性粒细胞白血病相关。我们的 实验室最近克隆了两个新的酪氨酸激酶融合基因，TEL- 与t(5；12)和t(9；12)相关的PDGFRbeta和tel-ABL 人类白血病中的染色体易位。电话是一种新的 Ets转录因子家族的成员，对 对两种融合都保守的螺旋-环-螺旋(HLH)结构域。的目标是 这项建议旨在确定电信转型的机制-- PDGFRbeta和TEL-ABL的泛函贡献分析 TEL、PDGFRbeta和ABL的结构域。我们假设这种转变是 由于PDGFRβ和ABL酪氨酸的异常表达和激活 由TELHLH域介导的激酶。初步研究表明 记录了融合蛋白的转化活性，并 证明PDGFR和ABL的酪氨酸激酶活性是绝对的 转型活动的要求。人促黄体生成素结构域在细胞内的作用 ETS的家庭成员尚不清楚。然而，对这些问题的初步分析 融合使我们有了一个有趣的发现：TELHLH域出现了 成为蛋白质-蛋白质相互作用的模体。这一发现与 观察到在TEL-ABL中另一个TEL等位基因被删除 白血病，并在TEL-PDGFRβ白血病中低水平表达，提示 TELL功能的丧失可能在白血病的发病机制中起重要作用。在……里面 具体目标1，我们将表征信号转导特性 TELL-PDGFRβ融合蛋白，并确定哪些是在 调停转型。在具体目标2中，我们将分析信号 TEL-ABL的转导特性，并确定其共同主位 统一了TEL-ABL和BCR-ABL的变换性质。具体目标3 将重点介绍TELHLH域在转换中的作用和 TEL功能丧失可能参与了糖尿病的发病机制 白血病。TEL-PDGFRβ转化机制的研究 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。

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.