STAT1 IS INDUCED AND ACTIVATED BY ALL-TRANS-RETINOIC ACID IN ACUTE PROMYELOCYTIC LEUKEMIA-CELLS

Treatment of freshly isolated acute promyelocytic leukemia (APL) cells and the myelogenous leukemia cell lines, NB4, HL-60, and U937, with a ll-trans retinoic acid (ATRA) results in a remarkable elevation in the amounts of Stat1 alpha and Stat2 proteins. Stat1 alpha protein levels are augmented by ATRA as a consequence of elevated amounts of the cor responding transcripts. The retinoid increases the levels of nuclear c omplexes that are capable of binding to interferon (IFN)-regulated con sensus sequences and contain Stat1 and/or Stat2 proteins, and causes a rapid and long-lasting elevation in Stat1 alpha tyrosine phosphorylat ion. Transient transfection experiments show that ATRA enhances the tr ansactivating properties of Stat1 alpha observed on an appropriate rep orter gene, in the presence of the RAR alpha retinoic acid receptor, b ut not in the presence of the PML-RAR protein. Treatment of NB4 cells with ATRA is associated with a remarkable upregulation of the two IFN- responsive genes IFN-responsive factor 1 and 2'-5' oligoadenylate synt hetase, as well as with an augmentation in the levels of IFN alpha sec retion. Our data show that ATRA is capable of modulating the amounts a nd the state of activation of some of the components of the IFN intrac ellular signaling pathways. They also suggest that the retinoid can by pass IFN/IFN-receptor interactions and induce the expression of IFN-re gulated genes. (C) 1997 by The American Society of Hematology.