Ezh2 loss promotes the transformation of early T cell precursor ALL via suppressing critical genes for T-cell differentiation

Early T cell precursor (ETP) acute lymphoblastic leukemia (ALL) has been identified as a new pathologic entity with poor outcome in patients with T-ALL. In contrast to cortical T-ALL, ETP-ALL has been characterized by the activating mutations in genes regulating cytokine signaling and the alterations in the polycomb repressor complex 2 (PRC2) components, including EZH2. To investigate how EZH2 alterations promote the development of ETP-ALL, we generated a novel mouse model of ETP-ALL by utilizing Ezh2 and Trp53 conditional knockout mice. Ezh2/p53-dificient ETP-ALL cells significantly repressed expression of genes critical for T-cell commitment including Bcl11b and Tcf7, but elevated levels of expression in both HSCs and myeloid cells signature genes. Despite the repressed expression, H3K27me3 marks kept at obviously lower levels at the promoter regions of T-cell differentiation regulators in Ezh2/p53-dificient ETP leukemic cells. We demonstrated that altered DNA hypermethylation contributed to silencing the expression of T-cell differentiation regulators. In deed, treatment of decitabine, a demethylating agent, clearly induced the differentiation of Ezh2/p53-dificient ETP leukemic cells into mature T-cells. Thus, we underlined that combined deletions of Ezh2 and p53 altered the epigenetic regulation to an extent not seen in either deletion alone, and induced highly penetrant ETP-ALL characterized by the molecular profile seen in patients with ETP-ALL.