DIFFERENTIAL ACTION OF DIFFUSIBLE MOLECULES IN LONG-TERM MARROW CULTURE ON PROLIFERATION OF LEUKEMIC AND NORMAL HEMATOPOIETIC-CELLS

The capacity of diffusible molecules in the fluid phase of long-term h uman bone marrow culture (LTMC) to exert preferential adverse effects on leukaemic relative to normal haemopoietic cells has been investigat ed. Responses of isolated cell populations were assessed in diffusion chamber inserts which permitted contact with fluid phase molecules but not with the adherent stromal cell layer of the LTMC system. Growth o f AML cells in diffusion chambers was inhibited during co-culture with LTMC of autologous leukaemic bone marrow, and the same effect was pro duced during co-culture with normal LTMC. No inhibitory action was exe rted on growth of normal haemopoietic precursors under the same condit ions. Comparable responses were observed with human leukaemic cell lin es and patient leukaemic cells, and studies on cell lines demonstrated inhibition of growth was induced by molecules generated in LTMC which caused accumulation in G1 phase of leukaemic cells of both myeloid an d lymphoid lineage. The inhibitory effect was not reproduced by TGFbet a, IFNgamma, IFNalpha, TNFalpha, LIF, SCF or Il-6, and was not impaire d by inhibitors of nitric oxide or PGE production in the LTMC. These o bservations suggest the action of diffusible molecules of undefined co nstitution contributes to the preferential loss of leukaemic cells in LTMC.