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Ezh2 loss propagates hypermethylation at T cell differentiation-regulating genes to promote leukemic transformation
- Source :
- Journal of Clinical Investigation. September, 2018, Vol. 128 Issue 9, p3872, 15 p.
- Publication Year :
- 2018
-
Abstract
- Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a new pathological entity with poor outcomes in T cell ALL (T-ALL) that is characterized by a high incidence of loss-of-function mutations in polycomb repressive complex 2 (PRC2) genes. We generated a mouse model of ETP-ALL by deleting Ezh2, one of the PRC2 genes, in p53-null hematopoietic cells. The loss of Ezh2 in p53-null hematopoietic cells impeded the differentiation of ETPs and eventually induced ETP-ALL-like disease in mice, indicating that PRC2 functions as a bona fide tumor suppressor in ETPs. A large portion of PRC2 target genes acquired DNA hypermethylation of their promoters following reductions in H3K27me3 levels upon the loss of Ezh2, which included pivotal T cell differentiation-regulating genes. The reactivation of a set of regulators by a DNA-demethylating agent, but not the transduction of single regulator genes, effectively induced the differentiation of ETP-ALL cells. Thus, PRC2 protects key T cell developmental regulators from DNA hypermethylation in order to keep them primed for activation upon subsequent differentiation phases, while its insufficiency predisposes ETPs to leukemic transformation. These results revealed a previously unrecognized epigenetic switch in response to PRC2 dysfunction and provide the basis for specific rational epigenetic therapy for ETP-ALL with PRC2 insufficiency.<br />Introduction Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as a new pathological entity of T cell ALL (T-ALL) that shows resistance to conventional chemotherapies and has [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 128
- Issue :
- 9
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.553759912
- Full Text :
- https://doi.org/10.1172/JCI94645