ALL-TRANS-RETINOIC ACID AND CYCLIC ADENOSINE-MONOPHOSPHATE COOPERATE IN THE EXPRESSION OF LEUKOCYTE ALKALINE-PHOSPHATASE IN ACUTE PROMYELOCYTIC LEUKEMIA-CELLS

Treatment of acute promyelocytic leukemia (APL) blasts with cyclic ade nosine monophosphate (cAMP) analogs, in combination with all-trans ret inoic acid (ATRA). results in the upregulation of the expression of le ukocyte alkaline phosphatase (LAP), a marker for the differentiation o f the granulocyte. The synergistic interaction between the cyclic nucl eotide analogs and the retinoid is not unique to APL cells. as it is o bserved also in the peripheral granulocytes of chronic myelogenous leu kemia (CML) patients. The molecular mechanisms underlying LAP inductio n were studied in NB4, an immortalized APL cell line. Induction of LAP enzymatic activity is dependent on the time of exposure and on the co ncentrations of dibutyryl-cAMP or 8-bromo-cAMP and ATRA, two factors t hat influence the kinetics of appearance of detectable levels of the e nzyme. Augmentation of LAP levels by ATRA and cAMP is the result of bo th transcriptional and early posttranscriptional events and requires d e novo protein synthesis. LAP induction correlates with augmentation i n the levels of the type I catalytic subunit of cAMP-dependent protein kinase transcript and with granulocytic differentiation. The transcri ptional component of the process leading to increased LAP gene express ion was reproduced in its main features by transient transfection expe riments performed in COS-7 cells using the normal retinoic acid recept or type alpha (RAR-alpha) or the APL-specific aberrant form (PML-RAR)a nd the upstream promoter of the liver/ bone/kidney (L/B/K)-type alkali ne phosphatase gene. The promoter is upregulated by treatment with ATR A, and this upregulation is further increased by cAMP analogs. (C) 199 5 by The American Society of Hematology.