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T-cell acute lymphoblastic leukemia is a highly heterogeneous and aggressive entity within hematological malignancies, characterized by a poor prognosis, especially for refractory or relapsed cases. The multiple and complex oncogenic processes make it difficult to identify effective targeted therapies for all patients. The most immature forms of the disease frequently contain alterations in epigenetic regulators that enable the identification of patients with a poor prognosis and who are as such eligible for treatment with hypomethylating agents. Furthermore, our recent work reveals that loss of function of the Polycomb complex PRC2 is accompanied by a profound remodeling of the epigenetic landscape of blasts and gives synthetic lethality to targeting bromodomain proteins. In the era of personalized medicine, understanding epigenetic deregulations in leukemias enables the development of new effective targeted therapies for patients.