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Cancer Procoagulant and Tissue Factor Are Differently Modulated
by All-trans-Retinoic Acid in Acute Promyelocytic Leukemia
Cells
A. Falanga,
R. Consonni,
M. Marchetti,
G. Locatelli,
E. Garattini,
C. Gambacorti Passerini,
S.G. Gordon, and
T. Barbui
From the Hematology Division, Ospedali Riuniti, Bergamo; Mario Negri
Institute for Pharmacological Research, Milan; Istituto Nazionale
Tumori, Milan, Italy; and the Department of Biology, San Diego State
University, San Diego, CA.
All-trans-retinoic acid (ATRA) downregulates the expression
of two cellular procoagulants, tissue factor (TF) and cancer
procoagulant (CP), in human promyelocytic leukemia cells. To evaluate
whether or not changes of the procoagulant activities (PCAs) may share mechanisms with the ATRA-induced cyto-differentiation process, we have
characterized the effect of ATRA on the TF and CP expression by NB4
cells, an ATRA maturation-inducible cell line, and two NB4-derived cell
lines resistant to ATRA-induced maturation, the NB4.306 and NB4.007/6
cells. Next, we evaluated the effect on the PCAs of the NB4 parental
cells of three synthetic retinoid analogues, ie: AM580 (selective for
the retinoic acid receptor [RAR]  ), capable to induce
the granulocytic differentiation of NB4 cells; and CD2019 (selective
for RAR ) and CD437 (selective for RAR ), both lacking this
capability. Cells were treated with either ATRA or the analogues
(10 6 to 108 mol/L) for 96 hours. The
effect on cell differentiation was evaluated by morphologic changes,
cell proliferation, nitro blue tetrazolium reduction assay, and flow
cytometry analysis of the CD33 and CD11b surface-antigen expression.
PCA was first measured in 20 mmol/L Veronal Buffer cell extracts by the
one-stage clotting assay of normal and FVII-deficient plasmas. Further
TF and CP have been characterized and quantified in cell-sample
preparations by chromogenic and immunological assays. In the first
series of experiments, ATRA downregulates both TF and CP in NB4
parental cells, as expected. However, in the differentiation-resistant
cell lines, it induced a significant loss of TF but had little or no
effect on CP. In a second series of experiments, in the NB4 parental
cells, the RAR agonist (AM580) induced cell maturation and reduced
91% CP expression, whereas CD437 and CD2019 had no
cyto-differentiating effects and did not affect CP levels. On the other
hand, in the same cells the TF expression was reduced by ATRA and
AM580, but also by the RAR agonist CD2019, which did not induce cell
maturation. These data indicate that in NB4 cells, ATRA modulation of
CP occurs in parallel with signs of cell differentiation, while the
regulation of TF appears to be at least in part independent from these
processes, and involves both and nuclear retinoid receptors.
Blood, Vol. 92 No. 1 (July 1), 1998:
pp. 143-151
© 1998 by The American Society of Hematology.
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