HUMAN LEUKEMIA AND THE BONE MARROW MICROENVIRONMENT

人类白血病和骨髓微环境

• 批准号: 2446825
• 负责人: Tucker W LeBien
• 金额: $ 19.43万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-05 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2446825
• 关键词: acute lymphocytic leukemia; biological signal transduction; bone marrow; cell growth regulation; cell line; cyclin dependent kinase; cyclins; flow cytometry; human subject; immunochemistry; laboratory mouse; ligands; receptor binding; retinoblastoma protein; western blottings

DESCRIPTION: Acute lymphoblastic leukemia (ALL) is a malignancy that most often represents the maturation arrest and clonal expansion of a Iymphoid precursor at a specific stage in early human B cell development. Despite impressive progress in delineating genetic abnormalities in ALL, the contribution of the abnormal proteins (e.g., fusion oncoproteins derived from chromosomal translocations) to the dysregulated growth of neoplastic B cell precursors is largely unknown. The last several years have witnessed an explosion of new knowledge regarding regulation of the cell cycle in mammalian cells. Major classes of molecules that play a fundamental role in positive and negative regulation of cell cycle progression have been discovered and characterized. These include the cyclin-dependent kinases (CDK) and their regulatory cyclin subunit partners, and two major classes of CDK inhibitors. Interestingly, one of the CDK inhibitor family members designated p16INK4 is deleted in 20-40% of cases of newly diagnosed ALL. Therefore, since p16INK4 has been shown to be a tumor suppressor gene in the mouse, a similar role for this protein may exist in ALL. Many human cancers, including ALL, respond to external growth stimuli in the context of the microenvironment wherein expansion of the neoplastic clone initially occurs. In the case of ALL, bone marrow stomal cells are probably a source of membrane-associated or extracellular matrix-associated survival/growth signals that are essential for expansion of the leukemic cells in vivo. The major goal of this application is to link bone marrow stromal cell-derived growth stimuli with dysregulated growth of ALL cells mediated by the cyclin DCDK/retinoblastoma (Rb) pathway. To our knowledge there are no reported models demonstrating that activation of the cyclin D/CDK/Rb pathway occurs in a tumor cell, following signaling mediated via direct cell-cell contact in a model that potentially recapitulates the microenvironment of the tumor. The applicants have established a pre-B ALL cell line, designated BLIN-2, that maintains a strict requirement on bone marrow stromal cells for survival and growth. This cell line will be used to: 1)characterize the role of the cyclin D/CDK/Rb pathway in bone marrow stromal cell-dependent growth, and 2) to identify and functionally characterize the ligand/receptor interactions that support the survival and growth of BLIN-2. Additional studies will determine the relevance of the BLIN-2 model to additional cases of ALL. The long-term goal of the project is to identify and characterize the bone marrow stromal cell ligands and their counter receptors on ALL cells that regulate the growth of this type of human cancer.

描述：急性淋巴细胞白血病(ALL)是一种最常见的恶性肿瘤 通常代表淋巴的成熟停止和克隆性扩张 人类早期B细胞发育特定阶段的前体。尽管 在描绘所有基因异常方面取得了令人印象深刻的进展， 异常蛋白(例如，衍生的融合癌蛋白)的贡献 从染色体易位)到肿瘤B的生长失调 细胞前体在很大程度上是未知的。在过去的几年里，见证了 关于细胞周期调控的新知识的爆炸性增长 哺乳动物细胞。起基础作用的分子的主要类别 细胞周期进程的正向和负向调节一直是 被发现并被表征。其中包括细胞周期蛋白依赖的蛋白激酶。 (CDK)和他们的调控周期蛋白亚单位伙伴，以及两大类 CDK抑制剂。有趣的是，CDK抑制剂家族成员之一 在20-40%的初诊ALL病例中，指定的p16INK4基因缺失。 因此，由于p16INK4已被证明是一种肿瘤抑制基因。 小鼠中，这种蛋白可能存在类似的作用。许多人类 癌症，包括ALL，在以下背景下对外部生长刺激做出反应 肿瘤性克隆最初扩增的微环境 发生。在ALL的情况下，骨髓干细胞可能是一个来源 膜相关或细胞外基质相关的生存/生长 对于体内白血病细胞的扩增至关重要的信号。这个 这项应用的主要目标是将骨髓基质细胞来源的 细胞周期蛋白介导的ALL细胞生长失调的生长刺激 DCDK/Rb通路。据我们所知，目前还没有报道 细胞周期蛋白D/CDK/Rb通路激活的模型 在肿瘤细胞中，通过细胞-细胞直接接触介导的信号转导 在一个可能重现肿瘤微环境的模型中。 申请者已经建立了一株Pre-B ALL细胞系，命名为Blin-2， 维持对骨髓基质细胞的严格要求 生存和成长。该细胞系将用于：1)表征 细胞周期蛋白D/CDK/Rb通路在骨髓基质细胞依赖性中的作用 生长，以及2)鉴定和功能表征配体/受体 支持BLIN-2生存和生长的相互作用。其他内容 研究将确定BLIN-2模型与其他病例的相关性 最重要的是。该项目的长期目标是确定和描述 急性淋巴细胞白血病的骨髓基质细胞配体及其受体 调节这种类型的人类癌症生长的细胞。