Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells

Activin A, one member of the transforming grow th factor (TGF)-beta superfa mily, is known to be a commitment factor for cell death and differentiation . In the present study, we demonstrate that human chronic myeloid leukemia (CML) cell lines, KU812 and K562 cells, either induced apoptosis or differe ntiation, respectively, by treatment with activin A. During these cell fate decisive events caused by activin A, rapid and transient up-regulation of Mcl-1 nas observed in both cell lines, In activin A-induced apoptosis of KU 812 cells, continuous up-regulation of Bas was observed. After the decrease in Mcl-1 expression had occurred, activation of caspase-9 and caspase-3 an d cleavage of DFF45 were shown to take place in KU812 cells, resulting in t he fragmentation of the genomic DNA of the cells. In contrast, the dean-reg ulation of Mcl-1 without up-regulation of Bas caused accumulation of hemogl obin (Hb) contents in activin A-treated K562 cells. Interestingly, erythrop oietin (EPO) prevented activin A-induced apoptosis with continuous expressi on of Mcl-1 and caused KU812 cells to undergo erythroid differentiation. To address the role of Mcl-1 in activin A-treated CML cells, KU812 and K562 c ells were stably transfected with cDNA encoding Mcl-1 (designated as KU812/ mcl and K562/mcl cells). As in combined effect of activin A and EPO on the parental KU812 cells, activin A induced differentiation, but not apoptosis, of KU812/mcl cells without modulating Bas levels. Activin A-treated K562/m cl cells, as well as parental cells, were only differentiated to erythroid cells, These results suggest that Mcl-1 is an early inducible gene activate d by the activin A signaling pathway for both cellular differentiation and apoptosis, and continuous expression of Mcl-1 mag be contributed to differe ntiation signals to the erythroid lineage in CML cells.