Pathobiologic Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. The incidence is increasing with global population ageing. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in MDS patients, their clinic...

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Published in:Cancer discovery 2018-08, Vol.8 (11), p.1438-1457
Main Authors: Hayashi, Yoshihiro, Zhang, Yue, Yokota, Asumi, Yan, Xiaomei, Liu, Jinqin, Choi, Kwangmin, Li, Bing, Sashida, Goro, Peng, Yanyan, Xu, Zefeng, Huang, Rui, Zhang, Lulu, Freudiger, George M., Wang, Jingya, Dong, Yunzhu, Zhou, Yile, Wang, Jieyu, Wu, Lingyun, Bu, Jiachen, Chen, Aili, Zhao, Xinghui, Sun, Xiujuan, Chetal, Kashish, Olsson, Andre, Watanabe, Miki, Romick-Rosendale, Lindsey E., Harada, Hironori, Shih, Lee-Yung, Tse, William, Bridges, James P., Caligiuri, Michael A., Huang, Taosheng, Zheng, Yi, Witte, David P., Wang, Qian-fei, Qu, Cheng-Kui, Salomonis, Nathan, Grimes, H. Leighton, Nimer, Stephen D., Xiao, Zhijian, Huang, Gang
Format: Article
Language:English
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Summary:Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. The incidence is increasing with global population ageing. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in MDS patients, their clinical features are quite similar. Here we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS-patient bone-marrow stem/progenitors. Major MDS-associated mutations ( Dnmt3a, Tet2, Asxl1, Runx1, and Mll1 ) activate the HIF1A signature. While inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS, and as an effective therapeutic target for a broad spectrum of MDS patients.
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-17-1203