canonical activities including either its non-histone methyltransferase activity or an independent-methyltransferase activity. In line with this, we revealed that non-canonical non-methyltransferase activity of EZH2 was associated with retinoic acid resistance in acute promyelocytic leukemia (APL) (Poplineau, Blood 2022) and we have recently extended our results to the context of non-APL acute myeloid leukemia (AML) resistant to chemotherapy. However, our current knowledge of how and which non-canonical activity of EZH2 participates to this process is still poorly understood. One of our hypotheses is that EZH2 posttranslational modifications (PTMs) and variation in its interacting partners would affect EZH2 activity and impact treatment response. By coupling proteomics, gene editing, epigenomics and transcriptomics approaches using AML cell line resistant to chemotherapy we are currently identifying and functionally characterizing EZH2 PTMs. We will monitor their repercussion at the chromatin and transcriptional level and study their impact on therapy response. Finally, we will evaluate, in preclinical models of AML, the therapeutic interest of targeting EZH2 non-canonical activity using an EZH2 PROTAC. We believe that EZH2 degradation will clear the therapy-resistant cells and/or lead to a transcriptomic reprogramming of these cells towards less aggressive cells. We hope to define AML conditions that will benefit the use of EZH2 degrader, opening new therapeutic opportunity for patients with high risk of relapse.