Beta CELL PROGENITORS AND BONE MARROW MICROENVIRONMENT

描述：（由申请人提供）B系急性淋巴细胞白血病 (ALL)是儿童最常见的癌症白血病淋巴母细胞 是B细胞祖细胞的克隆扩增， 微环境此类细胞及其正常对应细胞迅速死亡， 细胞凋亡，除非它们由基质层支持。根据以前 资金、适合维持未成熟B细胞和其他细胞的培养技术 造血细胞发育，参与相互作用的分子 未成熟B细胞和间质之间的差异。基质支持培养物 白血病B细胞前体使得测量白血病B细胞的生长 这些细胞的潜能、它们经历凋亡的倾向以及它们的 对抗癌药物敏感。 我们的长期目标是确定 正常和白血病细胞存活、生长和分化的要求 B细胞祖细胞，并将此信息应用于开发新的 ALL的治疗策略。微环境的细胞成分可以 有不同的能力支持生存和扩张的不成熟 淋巴样细胞在特定目标1中，将永生克隆基质细胞系 从淋巴造血的不同部位（人骨髓和 鼠性腺-中肾区）。细胞系的支持能力 然后将体外的未成熟B细胞和其它造血细胞 其特征在于，他们的血统协会确定。 具体目标2将解决基质细胞支持的机制， 未成熟淋巴样细胞存活。这些研究将以最近的报告为基础， 确定直接沟通重要性的初步调查结果 淋巴细胞和基质细胞之间的缝隙连接， 互动基因分析研究将用于确定是否 生长因子、粘附分子和其他潜在的 重要的分子与基质细胞系的能力有关， 支持淋巴样细胞。 特定目标3中的研究将使用基质支持的原代 白血病细胞进行临床前测试BAY 36 - 1677，一个基因 具有独特受体反应性和信号传导的IL-4工程变体 特性.在初步研究中，BAY 36 - 1677表现出强大的选择性， 对ALL细胞的细胞毒性，但不抑制正常 造血细胞，不影响成纤维细胞或内皮细胞。的 拟议的研究将进一步表征BAY的抗白血病活性 36 - 1677并鉴定协同相互作用的化合物。

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.