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HUMAN LEUKEMIA AND THE BONE MARROW MICROENVIRONMENT

人类白血病和骨髓微环境

基本信息

批准号：
6124490
负责人：
Tucker W LeBien
金额：
$ 20.23万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-12-05 至 2001-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6124490
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

项目摘要

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。通常代表淋巴组织的成熟停滞和克隆扩张人类早期 B 细胞发育特定阶段的前体。尽管在描述 ALL 遗传异常方面取得了令人瞩目的进展异常蛋白质的贡献（例如，融合癌蛋白衍生从染色体易位）到肿瘤 B 的生长失调细胞前体很大程度上是未知的。过去几年见证了关于细胞周期调节的新知识的爆炸式增长哺乳动物细胞。发挥基础作用的主要分子类别细胞周期进程的正向和负向调节被发现并表征。这些包括细胞周期蛋白依赖性激酶（CDK）及其调节细胞周期蛋白亚基伙伴，以及两大类 CDK抑制剂。有趣的是，CDK 抑制剂家族成员之一 20-40% 的新诊断 ALL 病例中指定的 p16INK4 被删除。因此，由于 p16INK4 已被证明是肿瘤抑制基因小鼠中，这种蛋白质可能存在于 ALL 中，具有类似的作用。许多人类癌症，包括 ALL，在以下情况下对外部生长刺激做出反应肿瘤克隆最初扩增的微环境发生。对于 ALL，骨髓造口细胞可能是一个来源膜相关或细胞外基质相关的存活/生长白血病细胞在体内扩增所必需的信号。这该应用的主要目标是将骨髓基质细胞衍生的细胞周期蛋白介导的生长刺激导致 ALL 细胞生长失调 DCDK/视网膜母细胞瘤 (Rb) 途径。据我们所知，没有报道模型证明发生了细胞周期蛋白 D/CDK/Rb 通路的激活在肿瘤细胞中，遵循通过直接细胞间接触介导的信号传导在一个可能重现肿瘤微环境的模型中。申请人已经建立了前 B ALL 细胞系，命名为 BLIN-2，对骨髓基质细胞保持严格的要求生存和成长。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，2) 识别配体/受体并对其进行功能表征支持 BLIN-2 生存和生长的相互作用。额外的研究将确定 BLIN-2 模型与其他病例的相关性全部。该项目的长期目标是确定和表征 ALL 上的骨髓基质细胞配体及其反受体调节此类人类癌症生长的细胞。