Ezh2 loss propagates hypermethylation at T cell differentiation-regulating genes to promote leukemic transformation

Changshan Wang, Motohiko Oshima, Daisuke Sato, Hirotaka Matsui, Sho Kubota, Kazumasa Aoyama, Yaeko Nakajima-Takagi, Shuhei Koide, Jun Matsubayashi, Makiko Mochizuki-Kashio, Takako Nakano-Yokomizo, Jie Bai, Toshitaka Nagao, Akinori Kanai, Atsushi Iwama, Goro Sashida

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3872-3886
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number9
DOIs
Publication statusPublished - 31-08-2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Medicine

Fingerprint

Dive into the research topics of 'Ezh2 loss propagates hypermethylation at T cell differentiation-regulating genes to promote leukemic transformation'. Together they form a unique fingerprint.

Cite this