The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion.
Nuclear bodies (NBs) are ultrastructurally defined granules predominantly found in dividing cells. Here we show that PML, a protein involved in the t(15;17) translocation of acute promyelocytic leukaemia (APL), is specifically bound to a NB. PML and several NB-associated proteins, found as auto-antigens in primary biliary cirrhosis (PBC), are co-localized and co-regulated. The APL-derived PML-RAR alpha fusion protein is shown to be predominantly localized in the cytoplasm, whereas a fraction is nuclear and delocalizes the NB antigens to multiple smaller nuclear clusters devoid of ultrastructural organization. RA administration (which in APL patients induces blast differentiation and consequently complete remissions) causes the re-aggregation of PML and PBC auto-antigens onto the NB, while PML-RAR alpha remains mainly cytoplasmic. Thus, PML-RAR alpha expression leads to a RA-reversible alteration of a nuclear domain. These results shed a new light on the pathogenesis of APL and provide a molecular link between NBs and oncogenesis.
Koken
M H
MH
CNRS UPR 43, Centre Hayem, Hôpital St Louis, Paris, France.
Puvion-Dutilleul
F
F
Guillemin
M C
MC
Viron
A
A
Linares-Cruz
G
G
Stuurman
N
N
de Jong
L
L
Szostecki
C
C
Calvo
F
F
Chomienne
C
C
D000818:Animals; D016466:CHO Cells; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D006224:Cricetinae; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D016253:Microscopy, Immunoelectron; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D014162:Transfection; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin