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Pathobiological Pseudohypoxia As a Putative Mechanism Underlying Myelodysplastic Syndromes

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Pathobiological Pseudohypoxia As a Putative Mechanism Underlying Myelodysplastic Syndromes Published OnlineFirst August 23, 2018; DOI: 10.1158/2159-8290.CD-17-1203 RESEARCH ARTICLE Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes Yoshihiro Hayashi1, Yue Zhang2, Asumi Yokota1, Xiaomei Yan1, Jinqin Liu2, Kwangmin Choi1, Bing Li2, Goro Sashida3, Yanyan Peng4, Zefeng Xu2, Rui Huang1, Lulu Zhang1, George M. Freudiger1, Jingya Wang2, Yunzhu Dong1, Yile Zhou1, Jieyu Wang1, Lingyun Wu1,5, Jiachen Bu1,6, Aili Chen6, Xinghui Zhao1, Xiujuan Sun2, Kashish Chetal7, Andre Olsson8, Miki Watanabe1, Lindsey E. Romick-Rosendale1, Hironori Harada9, Lee-Yung Shih10, William Tse11, James P. Bridges12, Michael A. Caligiuri13, Taosheng Huang4, Yi Zheng1, David P. Witte1, Qian-fei Wang6, Cheng-Kui Qu14, Nathan Salomonis7, H. Leighton Grimes1,8, Stephen D. Nimer15, Zhijian Xiao2, and Gang Huang1,2 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 chemi- cal 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); 1–20. ©2018 AACR. See related commentary by Chen and Steidl, p. 1355. 13 1Divisions of Pathology and Experimental Hematology and Cancer Biol- Ohio. The Ohio State University Comprehensive Cancer Center, Columbus, 14 ogy, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. 2State Ohio. Division of Hematology/Oncology, Aflac Cancer and Blood Disorders 15 Key Laboratory of Experimental Hematology, Institute of Hematology Center, Emory University School of Medicine, Atlanta, Georgia. Sylvester and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Comprehensive Cancer Center, University of Miami, Miami, Florida. Peking Union Medical College, Tianjin, China. 3International Research Note: Supplementary data for this article are available at Cancer Discovery Center for Medical Sciences, Kumamoto University, Chuo-ku, Kumamoto, Online (http://cancerdiscovery.aacrjournals.org/). 4 Japan. Division of Human Genetics, Cincinnati Children’s Hospital Medi- Current address for Y. Hayashi: Laboratory of Oncology, School of Life 5 cal Center, Cincinnati, Ohio. Department of Hematology, Sixth Hospital Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; 6 Affiliated to Shanghai Jiaotong University, Shanghai, China. Key Labora- and current address for Y. Zhang: Henan University of Chinese Medicine, tory of Genomic and Precision Medicine, Collaborative Innovation Center Henan, China. of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. 7Division of Biomedical Informatics, Z. Xiao and G. Huang jointly supervised this work. Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio. 8Division of Y. Hayashi, Y. Zhang, and A. Yokota contributed equally to this article. Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Corresponding Authors: Gang Huang, Cincinnati Children’s Hospital Medi- 9 Ohio. Laboratory of Oncology, School of Life Science, Tokyo University of cal Center, 3333 Burnet Avenue, Room S7.607, Cincinnati, OH 45229. 10 Pharmacy and Life Sciences, Tokyo, Japan. Department of Hematology and Phone: 513-636-3214; E-mail: [email protected]; and Zhijian Xiao, Oncology, Chang Gung Memorial Hospital-Linkou and Chang Gung University [email protected] College of Medicine, Taoyuan, Taiwan. 11James Graham Brown Cancer Center, University of Louisville Hospital, Louisville, Kentucky. 12Division of Pul- doi: 10.1158/2159-8290.CD-17-1203 monary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, ©2018 American Association for Cancer Research. OF1 | CANCER DISCOVERY NOVEMBER 2018 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst August 23, 2018; DOI: 10.1158/2159-8290.CD-17-1203 Activation of HIF1A Signaling by Pseudohypoxia in MDS RESEARCH ARTICLE INTRODUCTION reveal fundamental insights into MDS pathogenesis and pre- sent novel opportunities for therapeutic intervention beyond Myelodysplastic syndromes (MDS) are a group of hetero- specific mutations for MDS. geneous clonal disorders that are characterized by ineffective Hypoxia-inducible factor-1α (HIF1A) is a critical transcrip- hematopoiesis and unilineage or multilineage dysplasia (1, 2). tion factor for the hypoxic response, angiogenesis, normal Because of its diversity and complexity, the pathogenesis of HSC regulation, and cancer development (8, 9). Importantly, MDS remains to be elucidated. Limited preclinical models HIF1A is also essential for the activation of innate and are available for dissecting the pathogenesis and testing new adaptive immunity (10). HIF1A is regulated by both oxygen- drugs, and each model has its limitations (3, 4). Stem-cell dependent and oxygen-independent mechanisms (11). HSCs transplantation is a curative strategy for MDS; however, few and progenitor cells (HSPC) isolated from patients with MDS patients are eligible for transplantation. Further elucida- display abnormal self-renewal and differentiation, and accu- tion of the pathogenesis of MDS and development of novel mulating clinical and research evidence suggests an impor- therapeutic strategies are needed. MDS are associated with tant role for systemic inflammation and immune activation mutations in chromatin-modifying enzymes, splicing fac- in MDS pathogenesis (12). Thus, we tested the impact of HIF1A tors, transcription factors, cohesin complex, and metabolic sig naling in MDS. enzymes that regulate hematopoietic stem cell (HSC) self- renewal, survival, and differentiation. Cooperating genetic lesions occur, involving signaling molecules that regulate RESULTS cell growth and proliferation (1, 2, 5). Although a number of heterogeneous genomic aberrations have been identified Activated HIF1A Pathway in a Broad in patients with MDS (6, 7), their key clinical phenotypes are Spectrum of Patients with MDS similar. Therefore, we hypothesized that driver mutations HIF1A is mainly regulated at translational and protein activate common underlying mechanisms involved in MDS levels. Thus, analyzing downstream HIF1A signature gene phenotypes. Identification of these key mediators would expression is a reliable approach to measure HIF1A activation. NOVEMBER 2018 CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst August 23, 2018; DOI: 10.1158/2159-8290.CD-17-1203 RESEARCH ARTICLE Hayashi et al. To determine whether patients with MDS have an activated achieved doxycycline-inducible expression of both a stable HIF1A gene signature, we analyzed a published cohort of and constitutively active human HIF1A triple-point-mutant CD34+ bone marrow (BM) cells isolated from healthy donors (TPM; ref. 16) and wild-type (WT) ARNT (also known as (n = 17) or from patients with MDS (n = 183; ref. 13). This HIF1B, a subunit for dimerization with HIF1A; tet-on-TPM/ MDS cohort contains patients with refractory anemia (RA; ARNT; B6J/129 × 1 SvJ; Fig. 2A). After doxycycline admin- n = 55), refractory anemia with ring sideroblasts (RARS; n = istration, we found increased HIF1A protein expression 48), or refractory anemia with excess blast type 1 (RAEB1; n = in the c-KIT+ BM cells from Vav1-Cre/TPM mice (Fig. 2B). 37) or type 2 (RAEB2; n = 43). HIF1A regulates many genes, The resulting HIF1A protein expression level was 1.5-fold which could be either HIF1A direct targets or indirect tar- higher than in MllPTD/WT cells (Fig. 2C). To identify gene- gets (such as those regulated by HIF1A-regulated miRNAs). expression changes, we performed RNA-sequencing (RNA- The number of HIF1A-regulated genes exceeds 1,000 and seq) analysis of Vav1-Cre/TPM and wild-type c-KIT+ BM continues to increase (11). Notably, there are unique sets of cells. Pathway enrichment analysis revealed that a number target genes activated by HIF1A signaling in individual cell of HIF1A-related gene sets were significantly upregulated types (different lineage, at different maturation stage; ref. in the c-KIT+ BM cells from Vav1-Cre/TPM mice (Fig. 2D). 11). Recently, HIF1A-induced genes (which include both Notably, ARNT dimerizes not only with
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