Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders.
Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders.
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DOI：
10.1084/jem.20131144
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发表时间：
2013-11-18
期刊：
影响因子：
--
通讯作者：
Iwama A
中科院分区：
文献类型：
--
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
Ezh2 的缺失会导致发育调节基因的转录抑制、致癌性多梳靶标的抑制，以及小鼠中 MDS/MPN 样疾病的诱导，而 Tet2 的同时缺失会加剧这种疾病。多梳族 (PcG) 蛋白是造血干细胞的重要调节因子。最近对骨髓恶性肿瘤的广泛突变分析表明，PcG 基因（如 EZH2 和 ASXL1）的失活体细胞突变经常发生在骨髓增生异常性疾病患者中，包括骨髓增生异常综合征（MDS）和 MDS/骨髓增生性肿瘤（MPN）重叠性疾病（MDS/MPN）。在我们的患者队列中，还发现了 EZH2 突变，并且通常与四甲基胞嘧啶双加氧酶 2 (TET2) 突变同时发生。与这些发现一致的是，仅删除 Ezh2 就足以在小鼠中诱发 MDS/MPN 样疾病。此外，Ezh2 和 Tet2 的同时缺失会导致更严重的骨髓增生异常，并显着加速骨髓增生异常性疾病（包括 MDS 和 MDS/MPN）的发展。对造血祖细胞的全面全基因组分析表明，删除 Ezh2 后，关键发育调节基因的转录受到抑制，表明 Ezh1 进行补偿，而一组致癌的直接和间接多梳靶标则被去抑制。我们的研究结果提供了 EZH2 在骨髓恶性肿瘤中的肿瘤抑制功能的第一个证据，并强调了并发基因突变在骨髓增生异常性疾病发病机制中的协同作用。
Deletion of Ezh2 results in transcriptional repression of developmental regulator genes, derepression of oncogenic polycomb targets, and induction of MDS/MPN-like disease in mice that is exacerbated by concurrent deletion of Tet2. Polycomb group (PcG) proteins are essential regulators of hematopoietic stem cells. Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). In our patient cohort, EZH2 mutations were also found and often coincided with tet methylcytosine dioxygenase 2 (TET2) mutations. Consistent with these findings, deletion of Ezh2 alone was enough to induce MDS/MPN-like diseases in mice. Furthermore, concurrent depletion of Ezh2 and Tet2 established more advanced myelodysplasia and markedly accelerated the development of myelodysplastic disorders including both MDS and MDS/MPN. Comprehensive genome-wide analyses in hematopoietic progenitor cells revealed that upon deletion of Ezh2, key developmental regulator genes were kept transcriptionally repressed, suggesting compensation by Ezh1, whereas a cohort of oncogenic direct and indirect polycomb targets became derepressed. Our findings provide the first evidence of the tumor suppressor function of EZH2 in myeloid malignancies and highlight the cooperative effect of concurrent gene mutations in the pathogenesis of myelodysplastic disorders.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
DOI：
10.1084/jem.20111709
发表时间：
2012-03-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Oguro H;Yuan J;Tanaka S;Miyagi S;Mochizuki-Kashio M;Ichikawa H;Yamazaki S;Koseki H;Nakauchi H;Iwama A
通讯作者：
Iwama A
影响因子：
2.1
作者：
Chung, Young Rock;Schatoff, Emma;Abdel-Wahab, Omar
通讯作者：
Abdel-Wahab, Omar
体细胞突变改变生发中心起源的滤泡性和弥漫性大 B 细胞淋巴瘤中的 EZH2 (Tyr641)。
影响因子：
30.8
作者：
Morin, Ryan D.;Johnson, Nathalie A.;Severson, Tesa M.;Mungall, Andrew J.;An, Jianghong;Goya, Rodrigo;Paul, Jessica E.;Boyle, Merrill;Woolcock, Bruce W.;Kuchenbauer, Florian;Yap, Damian;Humphries, R. Keith;Griffith, Obi L.;Shah, Sohrab;Zhu, Henry;Kimbara, Michelle;Shashkin, Pavel;Charlot, Jean F.;Tcherpakov, Marianna;Corbett, Richard;Tam, Angela;Varhol, Richard;Smailus, Duane;Moksa, Michelle;Zhao, Yongjun;Delaney, Allen;Qian, Hong;Birol, Inanc;Schein, Jacqueline;Moore, Richard;Holt, Robert;Horsman, Doug E.;Connors, Joseph M.;Jones, Steven;Aparicio, Samuel;Hirst, Martin;Gascoyne, Randy D.;Marra, Marco A.
通讯作者：
Marra, Marco A.