Physical and functional interdependency between EZH2 and PLZF-RARA. (1) PLZF-RARA fusion stabilized the interaction of 2 PRC2 components, EZH2 and SUZ12, and the presence of EZH2 protected the fusion protein from degradation. (2) Targeting pan-EZH2 activity with its degrader, in combination with RA administration, induced restoration of RA sensitivity, cell differentiation and death, and transcriptional repression in cell cycle and DNA replication and prolonged survival of APL mice. (3) EZH2, as an enzymatic catalytic subunit of PRC2, posttranslationally trimethylates H3K27. However, inhibition of EZH2 enzymatic activity with small molecules did not reverse RA resistance. Replating capacity was sustained and cells were able to expand, which further resulted in leukemia progression. Professional illustration by Patrick Lane, ScEYEnce Studios.