Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation
Ezh2 loss propagates hypermethylation at T cell differentiation–regulating genes to promote leukemic transformation
复制标题
Ezh2 缺失会在 T 细胞分化过程中传播高甲基化，从而调节基因以促进白血病转化
DOI：
10.1172/jci94645
复制
发表时间：
2018-08
影响因子：
15.9
通讯作者：
Goro Sashida
中科院分区：
文献类型：
--
作者：
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
早期T细胞前体急性淋巴细胞白血病（ETP-ALL）是T细胞ALL（T-ALL）中一种预后不良的新病理实体，其特征是多梳抑制复合物2（PRC2）基因功能丧失突变的发生率高。我们通过删除 p53 缺失造血细胞中的 PRC2 基因之一 Ezh2，建立了 ETP-ALL 小鼠模型。 p53缺失造血细胞中Ezh2的缺失阻碍了ETP的分化，并最终在小鼠中诱发ETP-ALL样疾病，这表明PRC2在ETP中起到了真正的肿瘤抑制因子的作用。 Ezh2 缺失后 H3K27me3 水平降低，大部分 PRC2 靶基因的启动子发生 DNA 高甲基化，其中包括关键的 T 细胞分化调节基因。 DNA去甲基化剂重新激活一组调节因子，而不是单个调节基因的转导，有效诱导了ETP-ALL细胞的分化。因此，PRC2 保护关键的 T 细胞发育调节因子免受 DNA 高甲基化的影响，以使它们在随后的分化阶段做好激活准备，而它的不足会使 ETP 容易发生白血病转化。这些结果揭示了先前未被识别的针对 PRC2 功能障碍的表观遗传开关，并为针对具有 PRC2 缺陷的 ETP-ALL 进行特定合理的表观遗传治疗提供了基础。
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.
登录
查看更多内容
影响因子：
30.8
作者：
Zenatti PP;Ribeiro D;Li W;Zuurbier L;Silva MC;Paganin M;Tritapoe J;Hixon JA;Silveira AB;Cardoso BA;Sarmento LM;Correia N;Toribio ML;Kobarg J;Horstmann M;Pieters R;Brandalise SR;Ferrando AA;Meijerink JP;Durum SK;Yunes JA;Barata JT
通讯作者：
Barata JT
DOI：
10.1084/jem.20131144
发表时间：
2013-11-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Muto T;Sashida G;Oshima M;Wendt GR;Mochizuki-Kashio M;Nagata Y;Sanada M;Miyagi S;Saraya A;Kamio A;Nagae G;Nakaseko C;Yokote K;Shimoda K;Koseki H;Suzuki Y;Sugano S;Aburatani H;Ogawa S;Iwama A
通讯作者：
Iwama A
影响因子：
7
作者：
Maegawa S;Gough SM;Watanabe-Okochi N;Lu Y;Zhang N;Castoro RJ;Estecio MR;Jelinek J;Liang S;Kitamura T;Aplan PD;Issa JP
通讯作者：
Issa JP
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Mishima, Yuta;Wang, Changshan;Miyagi, Satoru;Saraya, Atsunori;Hosokawa, Hiroyuki;Mochizuki-Kashio, Makiko;Nakajima-Takagi, Yaeko;Koide, Shuhei;Negishi, Masamitsu;Sashida, Goro;Naito, Taku;Ishikura, Tomoyuki;Onodera, Atsushi;Nakayama, Toshinori;Tenen, Daniel G.;Yamaguchi, Naoto;Koseki, Haruhiko;Taniuchi, Ichiro;Iwama, Atsushi
通讯作者：
Iwama, Atsushi