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All-trans retinoic acid and cyclic adenosine monophosphate cooperate in the
expression of leukocyte alkaline phosphatase in acute promyelocytic
leukemia cells
M Gianni, M Terao, P Norio, T Barbui, A Rambaldi and E Garattini
Molecular Biology Unit, Centro Catullo e Daniela Borgomainerio, Istituto di
Ricerche Farmacologiche Mario Negri, Milan, Italy.
Treatment of acute promyelocytic leukemia (APL) blasts with cyclic
adenosine monophosphate (cAMP) analogs, in combination with all-trans
retinoic acid (ATRA), results in the upregulation of the expression of
leukocyte alkaline phosphatase (LAP), a marker for the differentiation of
the granulocyte. The synergistic interaction between the cyclic nucleotide
analogs and the retinoid is not unique to APL cells, as it is observed also
in the peripheral granulocytes of chronic myelogenous leukemia (CML)
patients. The molecular mechanisms underlying LAP induction were studied in
NB4, an immortalized APL cell line. Induction of LAP enzymatic activity is
dependent on the time of exposure and on the concentrations of
dibutyryl-cAMP or 8-bromo-cAMP and ATRA, two factors that influence the
kinetics of appearance of detectable levels of the enzyme. Augmentation of
LAP levels by ATRA and cAMP is the result of both transcriptional and early
posttranscriptional events and requires de novo protein synthesis. LAP
induction correlates with augmentation in the levels of the type I
catalytic subunit of cAMP- dependent protein kinase transcript and with
granulocytic differentiation. The transcriptional component of the process
leading to increased LAP gene expression was reproduced in its main
features by transient transfection experiments performed in COS-7 cells
using the normal retinoic acid receptor type alpha (RAR-alpha) or the APL-
specific aberrant form (PML-RAR) and the upstream promoter of the
liver/bone/kidney (L/B/K)-type alkaline phosphatase gene. The promoter is
upregulated by treatment with ATRA, and this upregulation is further
increased by cAMP analogs.
Volume 85,
Issue 12,
pp. 3619-3635,
06/15/1995
Copyright © 1995 by The American Society of Hematology
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