Epigenetic alterations are a major contributor to cancer, making epigenetic effectors interesting therapeutic targets. We will combine our efforts to elucidate the functions of an epigenetic enzyme, EZH2, which has a major and undisputed role in carcinogenesis and whose targeting offers hope, but whose function remains poorly understood. We still do not understand why, depending on the tumor, it plays a tumor suppressor or oncogenic role.

The ambivalence of EZH2 could be explained by differences in activity, modulated according to tissue and cellular context. In addition to its function as an enzymatic component of the repressive polycomb complex 2 (PRC2), characterized by the deposition of the epigenetic repressive mark of trimethylation of histone H3 at lysine 27 (H3K27me3), EZH2 appears to have additional activities (known as non-canonical or EZH2-solo) which could explain its pleiotropic effects. We will draw on the different expertise of the consortium to address the issue of how to target this epigenetic molecule with complex activities in different hematological disorders.

We will combine proteomics, gene editing, metabolomics, epigenomics and transcriptomics analyses to (i) characterize these activities, which may lie in the variation of EZH2 interaction partners and kinase-related post-translational modifications. In order to link the newly defined non-canonical functions to specific leukemic conditions, we will test (ii) the impact of their alterations on the development of two types of leukemia: AML and B-ALL. Using preclinical models established in both countries, we will (iii) assess the therapeutic value of targeting the non-canonical activity of EZH2 in various leukemias. Overall, the identification of the molecular pathways leading to the contextual functions of EZH2, the identification of alterations in these pathways and their validation in preclinical models will be crucial for improving the diagnosis, prognosis and therapy of leukemia.