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.
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.
Rousselot
P
P
Laboratoire de Biologie Cellulaire Hématopoïétique, Hôpital Saint Louis, Paris, France.
Hardas
B
B
Patel
A
A
Guidez
F
F
Gäken
J
J
Castaigne
S
S
Dejean
A
A
de Thé
H
H
Degos
L
L
Farzaneh
F
F
D001483:Base Sequence; D001853:Bone Marrow / Q000737:chemistry / Q000648:ultrastructure; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002762:Cholecalciferol / Q000494:pharmacology; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D004273:DNA, Neoplasm / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics*; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D002762:Cholecalciferol; D014212:Tretinoin