The promyelocytic leukaemia protein PML is a tumor suppressor inactivated in acute promyelocytic leukaemia (APL). PML is essential for multiple apoptotic pathways and controls senescence induced by oncogenic activation. PML transcript undergoes alternative splicing to produce nuclear and cytoplasmic isoforms. The PML nuclear isoform IV interacts with p53 and potentiates its proapoptotic and growth suppressive functions. By contrast, the function of PML cytoplasmic isoforms is presently unknown.
Two PML mutants have been identified in APL, which lack the nuclear localization signal and the p53 interaction domain. We found that both the wild type and mutant forms of cytoplasmic PML reside in cytoplasmic bodies (PML-CB), which rely on the formation of PML oligomers. Mutant PML specifically delocalizes the acetyl-transferase CBP into the PML-CB, while it does not affect the localization of other PML-NB components such as DAXX and Sp100. PML-RAR itself co-localizes and interacts with mutant PML and causes the delocalization of CBP into the PML-CB. Remarkably, mutant PML, like PML-RAR, inhibits RA-dependent transcription. Overall, these findings uncover a novel function of PML in the cytoplasm and shed new light on the molecular mechanisms of APL.