Autocrine production and action of IL-3 and granulocyte colony-stimulatingfactor in chronic myeloid leukemia

Primitive subsets of leukemic cells isolated by using fluorescence-activate d cell sorting from patients with newly diagnosed Ph+/BCR-ABL(+) chronic my eloid leukemia display an abnormal ability to proliferate in vitro in the a bsence of added growth factors. We now show from analyses of growth-factor gene expression, protein production, and antibody inhibition studies that t his deregulated growth can be explained, at least in part, by a novel diffe rentiation-controlled autocrine mechanism. This mechanism involves the cons istent and selective activation of IL-3 and granulocyte colony-stimulating factor (G-CSF) production and a stimulation of STAT5 phosphorylation in CD3 4(+) leukemic cells. When these cells differentiate into CD34(-) cells in v ivo, IL-3 and C-CSF production declines, and the cells concomitantly lose t heir capacity for autonomous growth in vitro despite their continued expres sion of BCR-ABL Based on previous studies of normal cells, excessive exposu re of the most primitive chronic myeloid leukemia cells to IL-3 and G-CSF t hrough an autocrine mechanism could explain their paradoxically decreased s elf-renewal in vitro and slow accumulation in vivo, in spite of an increase d cycling activity and selective expansion of later compartments.