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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 establishthat 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 drivesboth efficient NCoR sumoylation and immortalization. Sumoylation inhibitors re-activate retinoic acid target genes in PML::RARA-, but not in RARA-, expressing progenitors and trigger APL differentiation. Thus, fusion of PML to RARA entails an unexpected gain of functionthat boosts RARA-mediated transcriptional repression through sumoylation of PML::RARA-bound proteins, explaining the recurrent implication of PML and RARA in APL pathogenesis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell

SUBMITTER: Viviane de Almeida Bastos

LAB HEAD: Hugues de Thé

PROVIDER: PXD078941 | Pride | 2026-08-04

REPOSITORIES: Pride

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			Action	DRS
	230719_ONCOBIND_1DE02_ech02_DIA_2uL_0.65-1.15_Slot1-20_1_8726.d.zip	Other
	230719_ONCOBIND_1DE02_ech05_DIA_2uL_0.65-1.15_Slot1-23_1_8734.d.zip	Other
	230719_ONCOBIND_1DE02_ech08_DIA_2uL_0.65-1.15_Slot1-26_1_8740.d.zip	Other
	230719_ONCOBIND_1DE03_ech03_DIA_2uL_0.65-1.15_Slot1-12_1_8712.d.zip	Other
	230719_ONCOBIND_1DE03_ech06_DIA_2uL_0.65-1.15_Slot1-15_1_8706.d.zip	Other

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