期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 9, 页码 3872-3886出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI94645
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [15H02544, 25130702, 26461396, 16KT0113, 22118004, 26115002]
- Program of Higher-Level Talents of Inner Mongolia University award
- National Natural Science Foundation of China [81660024]
- Grants-in-Aid for Scientific Research [26461396, 15H02544, 22118004, 16KT0113] Funding Source: KAKEN
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.
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