Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation

Wonhyoung Seo; Seungyeul Yoo; Yi Zhong; Sang-Hee Lee; Soo-Yeon Woo; Hee-Seon Choi; Minho Won; Taylor Roh; Sang Min Jeon; Kyeong Tae Kim; Prashanta Silwal; Min Joung Lee; Jun Young Heo; Nathan Lawlor; Sup Kim; Dongjun Lee; Jin-Man Kim; Ik-Chan Song; Jun Zhu; Eun-Kyeong Jo

doi:10.1186/s13045-022-01372-7

Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation

J Hematol Oncol. 2022 Oct 26;15(1):156. doi: 10.1186/s13045-022-01372-7.

Authors

Wonhyoung Seo^#^{1

2}, Seungyeul Yoo^#³, Yi Zhong³, Sang-Hee Lee⁴, Soo-Yeon Woo⁵, Hee-Seon Choi⁵, Minho Won⁶, Taylor Roh^{1

2}, Sang Min Jeon^{1

2}, Kyeong Tae Kim^{1

2}, Prashanta Silwal^{1

2}, Min Joung Lee⁷, Jun Young Heo⁷, Nathan Lawlor³, Sup Kim⁸, Dongjun Lee⁵, Jin-Man Kim^{1

2

9}, Ik-Chan Song^#¹⁰, Jun Zhu^#^{11

12}, Eun-Kyeong Jo^#^{13

14}

Affiliations

¹ Department of Medical Science and Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea.
² Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea.
³ Sema4, Stamford, CT, USA.
⁴ Center for Research Equipment, Korea Basic Science Institute, Cheongju, South Korea.
⁵ Department of Convergence Medicine, School of Medicine, Pusan National University, Yangsan, South Korea.
⁶ Biotechnology Process Engineering Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, South Korea.
⁷ Department of Biochemistry, Chungnam National University College of Medicine, Daejeon, South Korea.
⁸ Department of Radiation Oncology, Chungnam National University Hospital, Daejeon, South Korea.
⁹ Department of Pathology, Chungnam National University College of Medicine, Daejeon, South Korea.
¹⁰ Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, South Korea. [email protected].
¹¹ Sema4, Stamford, CT, USA. [email protected].
¹² Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
¹³ Department of Medical Science and Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea. [email protected].
¹⁴ Infection Control Convergence Research Center, Chungnam National University College of Medicine, Daejeon, South Korea. [email protected].

^# Contributed equally.

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood. In this study, we investigated the oncogenic functions of ERRα in AML by combining in silico, in vitro, and in vivo analyses and showed ERRα is a key regulator of mtOXPHOS in AML cells. The increased ERRα level was associated with worse clinical outcomes of AML patients. Single cell RNA-Seq analysis of human primary AML cells indicated that ERRα-expressing cancer cells had significantly higher mtOXPHOS enrichment scores. Blockade of ERRα by pharmacologic inhibitor (XCT-790) or gene silencing suppressed mtOXPHOS and increased anti-leukemic effects in vitro and in xenograft mouse models.

Keywords: AML; Apoptosis; ERRα; Mitochondrial oxidative phosphorylation.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Apoptosis
Cell Line, Tumor
Cell Proliferation
ERRalpha Estrogen-Related Receptor
Humans
Leukemia, Myeloid, Acute* / genetics
Mice
Mitochondria / metabolism
Oxidative Phosphorylation

Substances

Antineoplastic Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding