Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes

• Published in: Cancer discovery 2018-11, 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
• Subjects: Animals; Core Binding Factor Alpha 2 Subunit - physiology; Gene Expression Regulation, Neoplastic; Histone-Lysine N-Methyltransferase - physiology; Humans; Hypoxia - physiopathology; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Metabolome; Mice; Mice, Knockout; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - pathology; Myeloid-Lymphoid Leukemia Protein - physiology
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.cd-17-1203

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. Their incidence is increasing with global population aging. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in patients with MDS, 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 ( , and ) activate the HIF1A signature. Although 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 patients with MDS. We showed that dysregulation of HIF1A signaling could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver mutations. This could resolve the disconnection between genotypes and phenotypes and provide a new clue as to how a variety of driver mutations cause common MDS phenotypes. .