TYROSINE KINASES BUT NOT CAMP-DEPENDENT PROTEIN-KINASE MEDIATE THE INDUCTION OF LEUKOCYTE ALKALINE-PHOSPHATASE BY GRANULOCYTE-COLONY-STIMULATING FACTOR AND RETINOIC ACID IN ACUTE PROMYELOCYTIC LEUKEMIA-CELLS

Leukocyte alkaline phosphatase (LAP) is synergistically induced by the combination of all-trans retinoic acid (ATRA) and granulocyte-colony- stimulating factor (G-CSF) in acute promyelocytic leukemia (APL) cells (Gianni' M. et al., Blood 83: 1909-1921, 1994). The role of cAMP and tyrosine kinases in the induction of LAP was investigated. In the APL cell line NB4, adenosine-3': 5'-monophosphothioate, cyclic, Rp isomer, a reversible inhibitor of cAMP-dependent protein kinase (PKA), has no effect on the induction of LAP enzymatic activity and mRNA triggered by ATRA + G-CSF, in conditions where this compound completely blocks t he upregulation of LAP transcript caused by the combination of the PKA agonist, dibutyryl-cAMP (db-cAMP), and ATRA. Challenge of NB4 cells w ith G-CSF, dbcAMP and ATRA causes a much higher induction of LAP relat ive to that observed in the presence of ATRA + G-CSF or ATRA + dbcAMP. Treatment of NB4 with ATRA and G-CSF results in increases in tile tyr osine phosphorylation of several proteins. In the presence of the cyto kine and the retinoid, tyrosine kinase inhibitors decrease LAP enzymat ic activity and mRNA. (C) 1995 Academic Press, Inc.