RETINOIC ACID INDUCES SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT)-1, STAT2, AND P48 EXPRESSION IN MYELOID-LEUKEMIA CELLS AND ENHANCES THEIR RESPONSIVENESS TO INTERFERONS

IFNs are antiproliferative cytokines that have growth-inhibitory effec ts on various normal and malignant cells. Therefore, they have been us ed in the treatment of certain forms of cancer, such as chronic myelog enous leukemia and hairy cell leukemia, However, there is little evide nce that IFNs would be effective in the treatment of acute myelogenous leukemia, and molecular mechanisms underlying IFN unresponsiveness ha ve not been clarified. Here we have studied the activation and inducti on of IFN-specific transcription factors signal transducer and activat or of transcription (STAT) 1, STAT2, and p48 in all-trans-retinoic aci d (ATRA)-differentiated myeloid leukemia cells using promyelocytic NB4 , myeloblastic HL-60, and monoblastic U937 cells as model systems. The se cells respond to ATRA by growth inhibition and differentiation, We show that in undifferentiated NB4 cells, 2',5'-oligoadenylate syntheta se and MxB gene expression is not activated by IFN-alpha, possibly due to a relative lack of signaling molecules, especially p48 protein, Ho wever, during ATRA-induced differentiation, steady-state STAT1, STAT2, and especially p48 mRNA and corresponding protein levels were elevate d both in NB4 and U937 cells, apparently correlating to an enhanced re sponsiveness of these cells to IFNs, ATRA treatment of NB4 cells sensi tized them to IFN action as seen by increased IFN-gamma activation sit e DNA-binding activity or by efficient formation of IFN-alpha-specific ISGF3 complex and subsequent oligoadenylate synthetase and MxB gene e xpression, Lack of p48 expression could be one of the mechanisms of pr omyelocytic leukemia cell escape from growth-inhibitory effects of IFN -alpha.