MONOCYTIC DIFFERENTIATION OF HL-60 PROMYELOCYTIC LEUKEMIA-CELLS CORRELATES WITH THE INDUCTION OF BCL-X(L)

Treatment of human promyelocytic leukemia HL-60 cells with phorbol est ers ultimately induces the differentiation of these cells along the mo nocyte/macrophage lineage, whereas treatment with retinoic acid or DMS O induces granulocytic/neutrophillic differentiation. In this study, w e demonstrate the disparate fates of HL-60 cells treated with the phor bol ester 12,13-phorbol dibutyric acid (PDBu) or DMSO, After DMSO trea tment, HL-60 cells eventually died via apoptosis, whereas the viabilit y of PDBu-treated cells was not affected during the same interval, The levels of the apoptosis effector proteins Bak and Bad were enhanced, whereas there was a slight down-regulation of the apoptosis suppressor protein Bcl-2 after treatment of the cells with PDBu and DMSO, Treatm ent with DMSO resulted in the elevation of the apoptosis effector Bar, whereas treatment with PDBu did not significantly alter the levels of this protein, However, treatment of HL-60 cells with PDBu induced the rapid expression of the apoptosis suppressor protein Bcl-x(L), wherea s the expression of this protein remained unaltered in DMSO-treated ce lls. The generality of this finding was confirmed by the induction of Bcl-x(L) in human myeloid U-937 cells, human peripheral blood monocyte s exposed to phorbol ester, and mouse thioglycollate-activated and res ident peritoneal macrophages. PDBu-treated HL-60 cells remained viable for 7 days and thereafter began to die via apoptosis, with a concomit ant down-regulation of Bcl-x(L). In conclusion, we propose that Bcl-x( L) expression is associated with differentiation and survival of hemat opoietic cells along the monocyte/macrophage lineage.