PML-driven sumoylation of PML/RARA-bound co-repressors drives immortalization of primary hematopoietic progenitors

Abstract While acute promyelocytic leukemia (APL) is always driven by fusions involving one of the three retinoic acid receptors, why PML and RARA are the preferred fusion partners has remained largely unsettled. Here we demonstrate that corepressor (NCoR) binding onto the RARA moiety of PML/RARA is required for hematopoietic progenitor immortalization. We then establish that PML-mediated tethering of the UBC9 SUMO conjugating enzyme onto PML/RARA enforces SUMO2 conjugation of multiple RARA partner proteins, notably the NCoR complex, boosting its repressive power. PML mutants that fail to recruit UBC9 yield PML/RARA fusions that neither promote NCoR sumoylation nor transformation. Conversely, direct UBC9/RARA fusion drives both efficient NCoR sumoylation and immortalization. Sumoylation inhibitors re-activate retinoic acid target genes in PML/RARA-, but not RARA-, expressing progenitors and trigger APL differentiation. Thus, fusion of PML to RARA entails an unexpected key gain of function that boosts RARA-mediated transcriptional repression through sumoylation of PML/RARA-bound protein, explaining the recurrent implication of PML and RARA in APL pathogenesis.