DRP003611
Ezh2 loss propagates pathogenic DNA hyper-methylation at T-cell commitment regulators and leads to the transformation of early T cell precursor ALL
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 CD8+ T-ALL, ETP-ALL has been characterized by loss-of-function mutations in the polycomb repressor complex 2 (PRC2) components, including EZH2.  To investigate how EZH2 alteration promotes the development of ETP-ALL, we generated a novel mouse model of CD8-c-Kit+CD44+ ETP-ALL by utilizing both Ezh2 and Trp53 conditional knockout mice.  Ezh2/p53-dificient thymic precursor cells impeded T-cell differentiation at transition from CD44+CD25+ (DN2) to CD44-CD25+ (DN3) stages, and significantly repressed expression of genes critical for T-cell development, but sustained expression of hematopoietic stem cells signature genes, resulting in the transformation of ETP-ALL.  Although Ezh2/p53-dificient ETP-ALL cells kept lower levels of H3K27me3 modification at these promoter regions, we found that aberrant DNA hyper-methylation contributed to repressing the transcription of T-cell commitment genes including Runx1 and Bcl11b.  Indeed, treatment of decitabine, a DNA demethylating agent, clearly induced the differentiation of ETP leukemic cells into mature T-cells, at least in part, due to restored expression of Runx1, of which loss-of-function mutations have been implicated in the pathogenesis of ETP-ALL.  Thus, we underlined that combined deletions of Ezh2 and p53 promoted a pathogenic epigenetic switch from H3K27me3 modification to DNA hyper-methylation at pivotal T-cell development genes, and induced highly penetrant ETP-ALL characterized by the phenotypic and transcriptional profiles seen in patients with ETP-ALL.