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.
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