B-CELL PROGENITORS AND BONE MARROW MICROENVIRONMENT

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B-lineage acute lymphoblastic leukemia (ALL) is the commonest form of leukemia in children. Leukemic cells express morphologic, phenotypic and genotypic features which appear identical to those of B lymphocyte progenitors in normal bone marrow (BM). Normal immature B cells and cells from most cases of B-lineage ALL rapidly die in vitro unless they are supported by BM-derived stromal feeder layers. the long-term objective of this research is to define the similarities and differences between the growth requirements of normal B cell progenitors and their neoplastic counterparts. This goal will be attempted through three interrelated specific aims: 1) define the stromal cell types supporting normal and leukemic human immature B cells; 2) identify the growth factors that affect survival, proliferation and differentiation of these cells on stromal feeder layers; 3) determine the cells and molecules essential for adhesion of immature B cells to BM stromal layers. The hypothesis underlying this research is that leukemic B-cell precursors can expand in microenvironments inadequate to sustain their normal counterparts. In Aim 1, the ability of BM stromal preparations grown under different culture conditions and of BM-derived stromal cell lines to support both normal and leukemic blast cells will be evaluated. In Aim 2, the first question to be addressed is whether the beneficial effects of BM stromal layers are mediated through soluble, membrane-bound or matrix-bound growth factors. The identification of the essential growth factors for leukemic cells and for normal B cells at various maturative stages will be attempted by testing the effects of either adding cytokines to the cultures or neutralizing their activity with specific antibodies. Aim 3 seeks to identify the adhesion molecules that play a central role in permitting the growth of normal and leukemic B- cell precursors on BM stromal layers, and to define the pattern of adhesion of normal B cells at various stages of maturation to different BM stromal cell components. The definition of the microenvironments that support normal and leukemic B-cell progenitors should increase understanding of B-cell ontogeny and leukemogenesis. It is also possible that new clinically relevant subgroups of patients will be identified on the basis of their in vitro growth requirements. The techniques established in this project should be applicable to in vitro models for testing of antileukemic agents.