Rescue from programmed cell death in leukemic and normal myeloid cells.

Growth factor-independent clones of myeloid leukemic cells can regain a growth factor-dependent state during differentiation. Loss of viability in these differentiating leukemic cells in the absence of growth factor was associated with DNA fragmentation and morphologic changes typical of programmed cell death (apoptosis). The differentiating leukemic cells could be rescued from apoptosis by a hematopoietic growth factor such as interleukin-3 (IL-3) and by the tumor-promoting phorbol ester 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), but not by the nonpromoting phorbol ester 4-alpha-TPA. IL-3 and TPA rescued differentiating myeloid leukemic cells by different pathways and also rescued normal myeloid precursor cells from apoptosis. The rescue of differentiating leukemic and normal myeloid cells by IL-3 or TPA was blocked by amiloride inhibitors of the Na+/H+ antiporter. We suggest that TPA may act as a tumor promoter by inhibiting programmed cell death.