THE T(1517) TRANSLOCATION ALTERS A NUCLEAR-BODY IN A RETINOIC ACID-REVERSIBLE FASHION

Nuclear bodies (NBs) are ultrastructurally defined granules predominan tly 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-lo calized and co-regulated. The APL-derived PML - RAR alpha fusion prote in is shown to be predominantly localized in the cytoplasm, whereas a fraction is nuclear and delocalizes the NB antigens to multiple smalle r nuclear clusters devoid of ultrastructural organization. RA administ ration (which in APL patients induces blast differentiation and conseq uently complete remissions) causes the re-aggregation of PML and PBC a uto-antigens onto the NB, while PML-RAR alpha remains mainly cytoplasm ic. Thus, PML-RAR alpha expression leads to a RA-reversible alteration of a nuclear domain. These results shed a new light on the pathogenes is of APL and provide a molecular link between NBs and oncogenesis.