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Adhesion molecules and differentiation syndrome: phenotypic and functional analysis of the effect of ATRA, As₂O₃, phenylbutyrate, and G-CSF in acute promyelocytic leukemia

From the Hematology Division and Center for Cell Based Therapy, Department of Internal Medicine (GCdS, MBT, RS, ABG, ASGL, RPF, EMR) and Department of Pharmacology (SEM, DS, FQC), Medical School of Ribeirão Preto, University of São Paulo, Brazil; Department of Clinical Analyses, Toxicology and Bromatology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil (LHF)

Correspondence: Eduardo M. Rego, Hematology Division, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Av. Bandeirantes 3900, CEP 14048-900 Ribeirão Preto, SP, Brazil. E-mail: emrego{at}hcrp.fmrp.usp.br

Background and Objectives: Differentiation Syndrome (DS) is a treatment complication which can occur in patients treated with acute promyelocytic leukemia (APL) with all transretinoic acid (ATRA) or As₂O₃, and is characterized by enhanced leukocyte transmigration. As₂O₃, Phenylbutyrate (PB) and G-CSF are known to potentiate ATRA effects. Our aim was to analyze the changes in expression and function of adhesion molecules induced by ATRA, As₂O₃, G-CSF and PB, and their association.

Design and Methods: APL blasts and NB4 cells were treated with ATRA, As₂O₃, PB, G-CSF or their association and the expression of adhesion molecules was determined by flow cytometry. Cell adhesion was evaluated in vitro using Matrigel and for the in vivo analysis, Balb-c mice were injected with NB4 cells pre-treated with ATRA, As₂O₃, ATRA+G-CSF or ATRA+As₂O₃. In addition, CD54 and CD18 knock-out mice were injected with NB4 cells and concomitantly treated with ATRA. In both models, the MPO activity in the lungs was determined 6 hours after the injection of the cells.

Results: In NB4 and APL blasts, ATRA and As₂O₃ increased CD54 expression, but no synergism was detected. CD11b and CD18 were also up-regulated by ATRA in primary cells. PB and G-CSF had no effect, but the latter potentiated ATRA-induced CD18 up-regulation. These changes were accompanied by increased adhesion to Matrigel and to lung microvasculature, and reversed by anti-CD54, anti-CD18 antibodies. In CD54 and CD18 knock-out mice the ATRA effect was canceled.

Interpretation and Conclusions: The use of As₂O₃, PB and G-CSF in association with ATRA should not aggravate DS in APL.

Key words: acute promyelocytic leukemia, adhesion molecules, histone deacetylase inhibitor, G-CSF.