望月　牧子
   Department   School of Medicine, School of Medicine
   Position   Assistant Professor
Article types Original article
Language English
Peer review Peer reviewed
Title Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders.
Journal Formal name：The Journal of experimental medicine
Abbreviation：J Exp Med
ISSN code：15409538/00221007
Domestic / ForeginForegin
Volume, Issue, Page 210(12),pp.2627-39
Author and coauthor Muto Tomoya, Sashida Goro, Oshima Motohiko, Wendt George R, Mochizuki-Kashio Makiko, Nagata Yasunobu, Sanada Masashi, Miyagi Satoru, Saraya Atsunori, Kamio Asuka, Nagae Genta, Nakaseko Chiaki, Yokote Koutaro, Shimoda Kazuya, Koseki Haruhiko, Suzuki Yutaka, Sugano Sumio, Aburatani Hiroyuki, Ogawa Seishi, Iwama Atsushi
Publication date 2013/11
Summary 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.
DOI 10.1084/jem.20131144
PMID 24218139