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（全部）是一种恶性肿瘤 通常代表二刺的成熟和克隆膨胀 在人类早期B细胞发育中的特定阶段的前体。 尽管 在描述遗传异常的情况下，令人印象深刻的进展， 异常蛋白质的贡献（例如，融合癌蛋白得出 从染色体易位）到肿瘤B的失调生长 细胞前体在很大程度上未知。 最近几年见证了 关于调节细胞周期的新知识的爆炸 哺乳动物细胞。 在 细胞周期进展的正和负调控已是 发现和表征。 这些包括依赖细胞周期蛋白的激酶 （CDK）及其调节性细胞周期蛋白亚基合作伙伴以及两个主要类别 CDK抑制剂。 有趣的是，CDK抑制剂家族成员之一 指定的P16INK4在20-40％的新诊断中被删除。 因此，由于P16INK4已被证明是肿瘤抑制基因 小鼠，该蛋白质的类似作用在所有人中都可能存在。 许多人 包括所有癌症，包括所有的癌症，在 最初肿瘤克隆膨胀的微环境 发生。 就所有情况而言，骨髓滞留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扩展至关重要的信号。 这 该应用的主要目标是将骨髓骨髓细胞衍生 生长刺激因细胞周期蛋白介导的所有细胞的生长失调而刺激 DCDK/视网膜母细胞瘤（RB）途径。 据我们所知，没有报道 模型表明激活细胞周期蛋白D/CDK/RB途径发生 在肿瘤细胞中，通过直接细胞接触介导的信号传导后 在可能概括肿瘤的微环境的模型中。 申请人已经建立了一个Pre-B全细胞系，指定为blin-2， 在骨髓基质细胞上保持严格要求 生存和成长。 该单元线将用于：1）表征 细胞周期蛋白D/CDK/RB途径在骨髓基质细胞依赖性中的作用 生长和2）识别并在功能上表征配体/受体 支持Blin-2的生存和生长的相互作用。 额外的 研究将确定Blin-2模型与其他情况的相关性 所有。 该项目的长期目标是识别和表征 骨髓基质细胞配体及其对抗受体 调节这种类型的人类癌的细胞。