B CELL PROGENITORS AND BONE MARROW MICROENVIRONMENT

描述：（改编自研究者摘要）B细胞前体 急性淋巴细胞白血病（ALL）是最常见的癌症形式， 孩子白血病淋巴母细胞是B细胞的克隆性扩增 在骨髓微环境中生长的祖细胞。很长的- 本提案的长期目标是定义体内要求 正常和白血病B细胞的存活、生长和分化 淋巴母细胞本申请中描述的培养系统使用 骨髓源性基质细胞预防未成熟B细胞凋亡 细胞并维持其体外生长。过去的成就 资助期包括直接接触基质的示范 是淋巴细胞存活所必需的， 几种分子参与了这种相互作用。此外，结扎 CD 38是一种跨膜糖蛋白，在未成熟的 发现B细胞抑制淋巴细胞生成。获得的信息 使我们能够开发出可能改善ALL治疗的检测方法。 也就是说，白血病细胞在基质上的生长与 治疗结果，提供检测白血病B敏感性的方法 淋巴母细胞的抗癌药物。 本申请的具体目标1和2侧重于微环境 调节B淋巴细胞生成的信号。认识到结扎 CD 38分子抑制B细胞生长并诱导其凋亡 前体已经建议进行研究以鉴定CD 38的天然配体， 并确定其组织分布和生理作用（目标1）。 由于观察到与基质的接触对于 未成熟B细胞存活，已经提出实验来鉴定 基质衍生的分子，其在这些细胞中触发抗凋亡信号， 细胞（目标2）。关于生存的信息 白血病B细胞前体的要求将被用于（目标3）， 解决了一个悬而未决的临床重要性问题：药物 体外敏感性试验对儿童预后有重要意义 全部？通过使用我们的基于基质的测定来支持长期生长 在ALL母细胞中，应该有可能与体外细胞 不同抗白血病药物的临床生物学反应 ALL和治疗结果。这项回顾性研究基于 所收集的关于每一名入学儿童的全面信息 治疗研究XII，比较所基于的临床试验。 定义调节正常和白血病B- 细胞祖细胞应该大大增加我们对B细胞 个体发育以及白血病发生。建立药物敏感性 具有预后相关性的检测可能会改善 ALL患者个体的药物选择。

DESCRIPTION: (adapted from the investigator's abstract) B cell precursor 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 bone marrow microenvironment. The long- term objective of this proposal is to define the in vivo requirements for survival, growth and differentiation of normal and leukemic B lymphoblasts. The culture system described in this application uses bone marrow-derived stromal cells to prevent apoptosis of immature B cells and sustains their growth in vitro. Achievements during the past funding period include the demonstration that direct contact with stroma is required for lymphoid cell survival, and the identification of several molecules involved in this interaction. Additionally, ligation of CD38, a transmembrane glycoprotein abundantly expressed on immature B cells, was found to suppress lymphopoiesis. The information gained has enabled us to develop assays that may improve the treatment of ALL. That is, the growth of leukemic cells on stroma correlated strongly with treatment outcome, providing a means to test sensitivity of leukemic B lymphoblasts to anticancer drugs. Specific Aim 1 and 2 of this application focus on the microenvironmental signals that regulate B lymphopoiesis. Recognition that ligation of the CD38 molecule inhibits cell growth and induces apoptosis in B-cell precursors has suggested studies to identify the natural ligand of CD38, and to define its tissue distribution and physiological role (Aim 1). As a result of the observation that contact with stroma is essential for immature B-cell survival, experiments have been proposed to identify the stroma-derived molecules that trigger anti-apoptotic signals in such cells (Aim 2). Information that has been gained about survival requirements of leukemic B- cell precursors will be used (in Aim 3) to address an unresolved question of clinical importance: does drug sensitivity testing in vitro have prognostic importance in childhood ALL? By using our stroma-based assay to support the long-term growth of ALL blasts, it should be possible to correlate in vitro cellular responses to different antileukemic drugs with clinicobiologic features of ALL and treatment outcome. This retrospective study banks on the comprehensive information collected on each child enrolled in Total Therapy Study XII, the clinical trial on which the comparison is based. Defining the molecular interactions that regulate normal and leukemic B- cell progenitors should greatly increase our understanding of B-cell ontogeny as well as leukemogenesis. Establishing a drug sensitivity assay with prognostic relevance could lead to improved rationales for drug selection in individual patients with ALL.