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Supplementary Methods from Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes

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posted on 2023-04-03, 21:23 authored by Yoshihiro Hayashi, Yue Zhang, Asumi Yokota, Xiaomei Yan, Jinqin Liu, Kwangmin Choi, Bing Li, Goro Sashida, Yanyan Peng, Zefeng Xu, Rui Huang, Lulu Zhang, George M. Freudiger, Jingya Wang, Yunzhu Dong, Yile Zhou, Jieyu Wang, Lingyun Wu, Jiachen Bu, Aili Chen, Xinghui Zhao, Xiujuan Sun, Kashish Chetal, Andre Olsson, Miki Watanabe, Lindsey E. Romick-Rosendale, Hironori Harada, Lee-Yung Shih, William Tse, James P. Bridges, Michael A. Caligiuri, Taosheng Huang, Yi Zheng, David P. Witte, Qian-fei Wang, Cheng-Kui Qu, Nathan Salomonis, H. Leighton Grimes, Stephen D. Nimer, Zhijian Xiao, Gang Huang

Supplementary Methods

Funding

Kyoto University Foundation

MDS Foundation

Cincinnati Children's Hospital Research Foundation

Leukemia Research Foundation

OCRA

NIH

National Natural Science Funds of China

CAMS Initiative Fund for Medical Sciences

Tianjin science and technology projects

Cystic Fibrosis Foundation

Ministry of Science and Technology, Taiwan

History

ARTICLE ABSTRACT

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 (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) 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.Significance: 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. Cancer Discov; 8(11); 1438–57. ©2018 AACR.See related commentary by Chen and Steidl, p. 1355.This article is highlighted in the In This Issue feature, p. 1333

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