Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

Goro Sashida (), Hironori Harada, Hirotaka Matsui, Motohiko Oshima, Makiko Yui, Yuka Harada, Satomi Tanaka, Makiko Mochizuki-Kashio, Changshan Wang, Atsunori Saraya, Tomoya Muto, Yoshihiro Hayashi, Kotaro Suzuki, Hiroshi Nakajima, Toshiya Inaba, Haruhiko Koseki, Gang Huang, Toshio Kitamura and Atsushi Iwama ()
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Goro Sashida: Graduate School of Medicine, Chiba University
Hironori Harada: Research Institute for Radiation Biology and Medicine, Hiroshima University
Hirotaka Matsui: Research Institute for Radiation Biology and Medicine, Hiroshima University
Motohiko Oshima: Graduate School of Medicine, Chiba University
Makiko Yui: Graduate School of Medicine, Chiba University
Yuka Harada: Research Institute for Radiation Biology and Medicine, Hiroshima University
Satomi Tanaka: Graduate School of Medicine, Chiba University
Makiko Mochizuki-Kashio: Graduate School of Medicine, Chiba University
Changshan Wang: Graduate School of Medicine, Chiba University
Atsunori Saraya: Graduate School of Medicine, Chiba University
Tomoya Muto: Graduate School of Medicine, Chiba University
Yoshihiro Hayashi: Cincinnati Children's Hospital Medical Center
Kotaro Suzuki: Graduate School of Medicine, Chiba University
Hiroshi Nakajima: Graduate School of Medicine, Chiba University
Toshiya Inaba: Research Institute for Radiation Biology and Medicine, Hiroshima University
Haruhiko Koseki: JST, CREST
Gang Huang: Cincinnati Children's Hospital Medical Center
Toshio Kitamura: Institute of Medical Science, University of Tokyo
Atsushi Iwama: Graduate School of Medicine, Chiba University

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract Loss-of-function mutations of EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), are observed in ~\n10% of patients with myelodysplastic syndrome (MDS), but are rare in acute myeloid leukaemia (AML). Recent studies have shown that EZH2 mutations are often associated with RUNX1 mutations in MDS patients, although its pathological function remains to be addressed. Here we establish an MDS mouse model by transducing a RUNX1S291fs mutant into hematopoietic stem cells and subsequently deleting Ezh2. Ezh2 loss significantly promotes RUNX1S291fs-induced MDS. Despite their compromised proliferative capacity of RUNX1S291fs/Ezh2-null MDS cells, MDS bone marrow impairs normal hematopoietic cells via selectively activating inflammatory cytokine responses, thereby allowing propagation of MDS clones. In contrast, loss of Ezh2 prevents the transformation of AML via PRC1-mediated repression of Hoxa9. These findings provide a comprehensive picture of how Ezh2 loss collaborates with RUNX1 mutants in the pathogenesis of MDS in both cell autonomous and non-autonomous manners.

Date: 2014
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DOI: 10.1038/ncomms5177

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