The PML-RAR alpha gene product of the t(15;17) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells.
Fiche publication
Date publication
février 1994
Journal
Oncogene
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GUIDEZ Fabien
Tous les auteurs :
Rousselot P, Hardas B, Patel A, Guidez F, Gäken J, Castaigne S, Dejean A, de Thé H, Degos L, Farzaneh F
Lien Pubmed
Résumé
Acute promyelocytic leukemia (APL) is characterized by an arrest of granulocytic differentiation and a reciprocal t(15;17) translocation fusing the PML gene to the retinoic acid receptor alpha (RAR alpha) gene. PML was recently identified as a potential transcription factor. In non hematopoietic cells, the transfected PML-RAR alpha product binds all trans retinoic acid and exhibits altered transactivating properties when compared with RAR alpha. A major question raised by these observations is whether PML-RAR alpha contributes to the inhibition of myeloid differentiation. We find that in myeloid cell lines responsive to retinoic acid, PML-RAR alpha blocks retinoic acid mediated transactivation and totally abrogates the retinoic acid mediated granulocytic differentiation. These findings strongly suggest that PML-RAR alpha may, by blocking normal retinoic acid dependent myeloid differentiation, participate in the leukemogenesis of APL. The fact that high doses of all-trans retinoic acid relieve the inhibitory effect of PML-RAR alpha corroborates the therapeutic effect of all-trans retinoic acid in APL patients.
Mots clés
Base Sequence, Bone Marrow, chemistry, Bone Marrow Cells, Cell Differentiation, drug effects, Cell Line, Cholecalciferol, pharmacology, Chromosomes, Human, Pair 15, Chromosomes, Human, Pair 17, DNA, Neoplasm, genetics, Dose-Response Relationship, Drug, Granulocytes, cytology, Humans, Leukemia, Promyelocytic, Acute, genetics, Molecular Sequence Data, Neoplasm Proteins, Nuclear Proteins, Promyelocytic Leukemia Protein, Receptors, Retinoic Acid, analysis, Recombinant Fusion Proteins, genetics, Retinoic Acid Receptor alpha, Transcription Factors, genetics, Transcriptional Activation, genetics, Transfection, Translocation, Genetic, genetics, Tretinoin, pharmacology, Tumor Cells, Cultured, Tumor Suppressor Proteins
Référence
Oncogene. 1994 02;9(2):545-51