Interferons induce normal and aberrant retinoic-acid receptors type alpha in acute promyelocytic leukemia cells: potentiation of the induction of retinoid-dependent differentiation markers.
Treatment of the acute promyelocytic (APL) cell line NB4 with interferon alpha (IFN(alpha)), as well as IFN(beta) and gamma, results in an increased expression of the transcripts coding for retinoic-acid receptor type alpha (RAR(alpha)) and the leukemia-specific retinoic acid receptor PML-RAR. Transcriptional induction of the RAR(alpha) and PML-RAR mRNAs is rapid and it is parallelled by an increase in the corresponding proteins. Up-regulation of RAR(alpha) and PML-RAR gene expression by IFN(alpha) is accompanied by a strong potentiation in the induction of 2 retinoid-dependent granulocytic markers, i.e., granulocyte-colony-stimulating factor receptor mRNA and leukocyte alkaline phosphatase. However, IFN(alpha) does not have any effects on the retinoid-dependent regulation of the myeloid surface markers CD11b and CD33. The IFN-dependent increase in RAR(alpha) levels and the enhancing effect of the cytokine on retinoid-dependent granulocytic markers expression may be a characteristic of PML-RAR positive cells, since the phenomena are not observed in HL-60 promyelocytes. Interferons as well as retinoids inhibit the growth of NB4 cells, although the 2 classes of compounds do not significantly interact in terms of anti-proliferative activity. These results suggest the possible use of combinations between IFNs and retinoic acid in the cyto-differentiating treatment of APL patients.
Molecular Biology Unit, Centro Catullo e Daniela Borgomainerio, Istituto di Ricerche Farmacologiche ¿Mario Negri¿, Milan, Italy.
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Gianní
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Zanotta
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Rambaldi
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Garattini
D000469:Alkaline Phosphatase / Q000378:metabolism; D002454:Cell Differentiation; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004357:Drug Synergism; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007372:Interferons / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D007962:Leukocytes / Q000201:enzymology; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012176:Retinoids / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D016179:Granulocyte Colony-Stimulating Factor; D003609:Dactinomycin; D014212:Tretinoin; D016899:Interferon-beta; D007371:Interferon-gamma; D007372:Interferons; D003513:Cycloheximide; D000469:Alkaline Phosphatase