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Cancer Discov. 2018 Nov;8(11):1438-1457. doi: 10.1158/2159-8290.CD-17-1203. Epub 2018 Aug 23.

Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes.

Author information

1
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
2
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
3
International Research Center for Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
4
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
5
Department of Hematology, Sixth Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.
6
Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
7
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
8
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
9
Laboratory of Oncology, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
10
Department of Hematology and Oncology, Chang Gung Memorial Hospital-Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan.
11
James Graham Brown Cancer Center, University of Louisville Hospital, Louisville, Kentucky.
12
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
13
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
14
Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia.
15
Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
16
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. Gang.Huang@cchmc.org zjxiao@hotmail.com.
17
Divisions of Pathology and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Gang.Huang@cchmc.org zjxiao@hotmail.com.
#
Contributed equally

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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