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Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders.

Authors: 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 
Citation: Muto T, etal., J Exp Med. 2013 Nov 18;210(12):2627-39. doi: 10.1084/jem.20131144. Epub 2013 Nov 11.
Pubmed: (View Article at PubMed) PMID:24218139
DOI: Full-text: DOI:10.1084/jem.20131144

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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CRRD Object Information
CRRD ID: 11038772
Created: 2016-02-24
Species: All species
Last Modified: 2016-02-24
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.