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; Atsushi Iwama

doi:10.1038/ncomms5177

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, Atsushi Iwama

Research output: Contribution to journal › Article › peer-review

127 Scopus citations

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.

Original language	English (US)
Article number	4177
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5177
State	Published - Jun 23 2014
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

Access to Document

10.1038/ncomms5177

Cite this

Sashida, G., Harada, H., Matsui, H., Oshima, M., Yui, M., Harada, Y., Tanaka, S., Mochizuki-Kashio, M., Wang, C., Saraya, A., Muto, T., Hayashi, Y., Suzuki, K., Nakajima, H., Inaba, T., Koseki, H., Huang, G., Kitamura, T., & Iwama, A. (2014). Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nature communications, 5, [4177]. https://doi.org/10.1038/ncomms5177

Sashida, G, Harada, H, Matsui, H, Oshima, M, Yui, M, Harada, Y, Tanaka, S, Mochizuki-Kashio, M, Wang, C, Saraya, A, Muto, T, Hayashi, Y, Suzuki, K, Nakajima, H, Inaba, T, Koseki, H, Huang, G, Kitamura, T & Iwama, A 2014, 'Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation', Nature communications, vol. 5, 4177. https://doi.org/10.1038/ncomms5177

@article{dbbda6c931124719ba7076163de2901c,

title = "Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation",

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.",

author = "Goro Sashida and Hironori Harada and Hirotaka Matsui and Motohiko Oshima and Makiko Yui and Yuka Harada and Satomi Tanaka and Makiko Mochizuki-Kashio and Changshan Wang and Atsunori Saraya and Tomoya Muto and Yoshihiro Hayashi and Kotaro Suzuki and Hiroshi Nakajima and Toshiya Inaba and Haruhiko Koseki and Gang Huang and Toshio Kitamura and Atsushi Iwama",

note = "Funding Information: We thank Dr Jun Matsubayashi for suggestions in histological analysis and members of the Iwama Laboratory for discussion during the preparation of this manuscript. This work was supported in part by Grants-in-aid for Scientific Research (#23591367, #24249054, #25130702) and Scientific Research on Innovative Areas {\textquoteleft}Cell Fate{\textquoteright} (#22118004) from MEXT, Japan, a Grant-in-aid for Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Corporation (JST) and grants from the Takeda Science Foundation, the Uehara Memorial Foundation and the Kanae Foundation.",

year = "2014",

month = jun,

day = "23",

doi = "10.1038/ncomms5177",

language = "English (US)",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation

AU - Sashida, Goro

AU - Harada, Hironori

AU - Matsui, Hirotaka

AU - Oshima, Motohiko

AU - Yui, Makiko

AU - Harada, Yuka

AU - Tanaka, Satomi

AU - Mochizuki-Kashio, Makiko

AU - Wang, Changshan

AU - Saraya, Atsunori

AU - Muto, Tomoya

AU - Hayashi, Yoshihiro

AU - Suzuki, Kotaro

AU - Nakajima, Hiroshi

AU - Inaba, Toshiya

AU - Koseki, Haruhiko

AU - Huang, Gang

AU - Kitamura, Toshio

AU - Iwama, Atsushi

N1 - Funding Information: We thank Dr Jun Matsubayashi for suggestions in histological analysis and members of the Iwama Laboratory for discussion during the preparation of this manuscript. This work was supported in part by Grants-in-aid for Scientific Research (#23591367, #24249054, #25130702) and Scientific Research on Innovative Areas ‘Cell Fate’ (#22118004) from MEXT, Japan, a Grant-in-aid for Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Corporation (JST) and grants from the Takeda Science Foundation, the Uehara Memorial Foundation and the Kanae Foundation.

PY - 2014/6/23

Y1 - 2014/6/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84903178102&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903178102&partnerID=8YFLogxK

U2 - 10.1038/ncomms5177

DO - 10.1038/ncomms5177

M3 - Article

C2 - 24953053

AN - SCOPUS:84903178102

VL - 5

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4177

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this