INTEGRIN SIGNALING IN ACUTE LYMPHOBLASTIC LEUKEMIA

急性淋巴细胞白血病中的整合素信号传导

• 批准号: 6174196
• 负责人: Arnold S. Freedman
• 金额: $ 16.65万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174196
• 关键词: B lymphocyte; apoptosis; biological signal transduction; bone marrow; cell adhesion molecules; cell cell interaction; cell cycle; cell differentiation; cell growth regulation; cell migration; cell proliferation; chemokine; clinical research; extracellular matrix; fibronectins; gene expression; human tissue; integrins; ligands; lymphocytic leukemia; phosphorylation; protein tyrosine kinase; tissue /cell culture; transfection

In acute lymphoblastic leukemia (ALL), interactions of leukemic cells with bone marrow (BM) stroma is mediated by members of the beta1 integrin family on leukemic cells, and their respective ligands in the marrow environment, specifically VCAM-1 on the BM stromal cells and fibronectin in the extracellular matrix. In addition to serving adhesive functions, one of the ways by which integrins can transduce signals is through the activation of tyrosine kinases, and ultimately to downstream pathways which regulate specific gene expression, proliferation, and migration of cells. In a variety of cell types, integrin mediated signaling has been shown to be critical to regulation of normal and malignant cells growth and the control of apoptosis. Over the past several years we have studied beta1 integrin mediated signal transduction as it related to neoplastic pre-B cells. We have identified and focused on the major substrates, specifically a docking/adaptor protein, HEF1, which appears to be important in both oncogenic and cell adhesive signaling pathways. Moreover, HEF1 probably functions as an intermediary between tyrosine kinase dependent signal transduction pathways and cell cycle regulation through its interaction with molecules which are relevant to cell cycle control and cell differentiation. In this proposal, we plan to extend our studies of integrin signaling in ALL cells and how the molecules involved in the signaling pathways regulate cell growth and survival. To this end, we plan to undertake three specific aims. First, to investigate the role of HEF1 during integrin signaling in pre-B ALL cells. Second, to determine the consequences of modulating beta1 integrin signaling pathways on growth, survival, adhesion and migration of pre-B cell ALL cells. Third, we will examine the effect of the bone marrow stromal cell derived chemokine, SDF-1 on integrin signaling pathways and function. We hypothesize that the regulation of HEF1 phosphorylation in integrin signaling plays a central role to the regulation of ALL proliferation, survival, and migration. Understanding the cell-cell interaction between BM stromal cells and pre-B ALL cells may provide future therapeutic strategies with which to modulate the growth of these leukemias.

在急性淋巴细胞白血病（ALL）中，白血病细胞与骨髓（BM）基质的相互作用是由白血病细胞上的β 1整合素家族成员及其在骨髓环境中各自的配体介导的，特别是BM基质细胞上的VCAM-1和细胞外基质中的纤维连接蛋白。除了具有粘附功能外，整合素转导信号的一种方式是通过激活酪氨酸激酶，并最终通过下游途径调节特定基因的表达、增殖和细胞的迁移。在多种细胞类型中，整合素介导的信号传导已被证明对正常和恶性细胞生长的调节以及细胞凋亡的控制至关重要。在过去的几年里，我们研究了β 1整合素介导的信号转导，因为它与肿瘤前b细胞有关。我们已经确定并专注于主要底物，特别是对接/适配器蛋白HEF1，它似乎在致癌和细胞粘附信号通路中都很重要。此外，HEF1可能通过与细胞周期控制和细胞分化相关分子的相互作用，在酪氨酸激酶依赖的信号转导途径和细胞周期调节之间起中介作用。在本提案中，我们计划扩展我们对ALL细胞中整合素信号通路以及参与信号通路的分子如何调节细胞生长和存活的研究。为此，我们计划实现三个具体目标。首先，研究HEF1在b ALL前细胞整合素信号传导中的作用。其次，确定调节β 1整合素信号通路对b细胞前ALL细胞生长、存活、粘附和迁移的影响。第三，我们将研究骨髓基质细胞来源的趋化因子SDF-1对整合素信号通路和功能的影响。我们假设整合素信号通路中HEF1磷酸化的调控在ALL增殖、存活和迁移的调控中起着核心作用。了解骨髓基质细胞和b前ALL细胞之间的细胞间相互作用可能为未来调节这些白血病的生长提供治疗策略。