Beta CELL PROGENITORS AND BONE MARROW MICROENVIRONMENT

β 细胞祖细胞和骨髓微环境

• 批准号: 6633073
• 负责人: DARIO CAMPANA
• 金额: $ 24.9万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633073
• 关键词: Animalia; B lymphocyte; acute lymphocytic leukemia; bone marrow; cell adhesion molecules; cell cell interaction; clinical research; gap junctions; growth factor; human subject; immunofluorescence technique; immunogenetics; immunopharmacology; interleukin 4; leukopoiesis; microarray technology; stem cells

DESCRIPTION: (provided by applicant) B-lineage acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. The leukemic lymphoblasts are clonal expansions of B-cell progenitors that grow within the hematopoietic microenvironment. Such cells and their normal counterparts rapidly die by apoptosis in vitro unless they are supported by stromal layers. Under previous funding, culture techniques suitable for maintaining immature B cells and other hematopoietic cells were developed, and molecules involved in the interaction between immature B cells and stroma identified. Stroma-supported cultures of leukemic B-cell precursors have made it possible to measure the growth potential of such cells, their propensity to undergo apoptosis and their sensitivity to anticancer drugs. Our long-term objective is to define the precise microenvironmental requirements for survival, growth and differentiation of normal and leukemic B-cell progenitors and to apply this information to the development of novel strategies of ALL treatment. Cellular components of the microenvironment may have different capacities for supporting the survival and expansion of immature lymphoid cells. In Specific Aim 1, immortal clonal stromal cell lines will be developed from different sites of lymphohematopoiesis (human bone marrow and murine aorta-gonad mesonephros region). The cell lines' ability to support immature B cells and other hematopoietic cells in vitro will then be characterized, and their lineage-association determined. Specific Aim 2 will address the mechanisms by which stromal cells support immature lymphoid cell survival. These studies will build on recent reports and preliminary findings to determine the importance of direct communication between lymphoid and stromal cells and the role of gap junctions in this interaction. Gene profiling studies will be used to determine whether expression of growth factors, adhesion molecules and other potentially important molecules is associated with the ability of stromal cell lines to support lymphoid cells. Studies in Specific Aim 3 will use stroma-supported cultures of primary leukemic cells to conduct preclinical testing of BAY 36-1677, a genetically engineered variant of IL-4 that has unique receptor-reactivity and signaling properties. In preliminary studies, BAY 36-1677 showed powerful and selective cytotoxicity against ALL cells but did not suppress the growth of normal hematopoietic cells and did not affect fibroblasts or endothelial cells. The proposed studies will further characterize the antileukemic activity of BAY 36-1677 and identify synergistically interacting compounds.

描述：（由申请人提供）B系急性淋巴细胞白血病 （ALL）是儿童中最常见的癌症形式。白血病淋巴母细胞 是在造血系统内生长的 B 细胞祖细胞的克隆扩增 微环境。这些细胞和它们的正常对应细胞很快就会死亡 体外细胞凋亡，除非它们得到基质层的支持。下一篇 资金、适合维持未成熟 B 细胞的培养技术和其他 造血细胞发育，参与相互作用的分子 未成熟 B 细胞和基质之间的鉴定。基质支持的培养物 白血病 B 细胞前体使测量生长成为可能 这些细胞的潜力、它们发生凋亡的倾向及其 对抗癌药物的敏感性。 我们的长期目标是定义精确的微环境 正常和白血病细胞生存、生长和分化的要求 B 细胞祖细胞并将这些信息应用于新型药物的开发 ALL 治疗策略。微环境的细胞成分可能 具有不同的能力来支持不成熟的生存和扩张 淋巴细胞。在具体目标 1 中，永生克隆基质细胞系将是 由淋巴造血的不同部位（人骨髓和 鼠主动脉-性腺中肾区）。细胞系的支持能力 未成熟的 B 细胞和其他造血细胞在体外将被 特征，并确定了它们的谱系关联。 具体目标 2 将解决基质细胞支持的机制 未成熟的淋巴细胞存活。这些研究将建立在最近的报告和 确定直接沟通重要性的初步调查结果 淋巴样细胞和基质细胞之间以及间隙连接在其中的作用 相互作用。基因谱研究​​将用于确定是否 生长因子、粘附分子和其他潜在的表达 重要的分子与基质细胞系的能力有关 支持淋巴细胞。 具体目标 3 的研究将使用基质支持的原代培养物 白血病细胞对 BAY 36-1677（一种基因药物）进行临床前测试 IL-4 的工程变体具有独特的受体反应性和信号传导 特性。在初步研究中，BAY 36-1677 显示出强大的选择性 对所有细胞具有细胞毒性，但不抑制正常细胞的生长 造血细胞，不影响成纤维细胞或内皮细胞。这 拟议的研究将进一步表征 BAY 的抗白血病活性 36-1677 并识别协同相互作用的化合物。