Up-regulation of ABCG1 is associated with methotrexate resistance in acute lymphoblastic leukemia cells

Yao Chen; Houshun Fang; Huiying Sun; Xiaoyu Wu; Yan Xu; Bin-Bing S Zhou; Hui Li

doi:10.3389/fphar.2023.1331687

Up-regulation of ABCG1 is associated with methotrexate resistance in acute lymphoblastic leukemia cells

Front Pharmacol. 2024 Jan 8:14:1331687. doi: 10.3389/fphar.2023.1331687. eCollection 2023.

Authors

Yao Chen¹, Houshun Fang¹, Huiying Sun¹, Xiaoyu Wu¹, Yan Xu¹, Bin-Bing S Zhou^{1

2

3}, Hui Li^{1

2}

Affiliations

¹ Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiaotong University School of Medicine, Fuzhou, China.
³ Department of Pharmacology and Chemical Biology, School of Basic Medicine and Shanghai Collaborative Innovation Center for Translational Medicine Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Acute lymphoblastic leukemia (ALL) is a prevalent hematologic malignancy in children, and methotrexate (MTX) is a widely employed curative treatment. Despite its common use, clinical resistance to MTX is frequently encountered. In this study, an MTX-resistant cell line (Reh-MTXR) was established through a stepwise selection process from the ALL cell line Reh. Comparative analysis revealed that Reh-MTXR cells exhibited resistance to MTX in contrast to the parental Reh cells. RNA-seq analysis identified an upregulation of ATP-binding cassette transporter G1 (ABCG1) in Reh-MTXR cells. Knockdown of ABCG1 in Reh-MTXR cells reversed the MTX-resistant phenotype, while overexpression of ABCG1 in Reh cells conferred resistance to MTX. Mechanistically, the heightened expression of ABCG1 accelerated MTX efflux, leading to a reduced accumulation of MTX polyglutamated metabolites. Notably, the ABCG1 inhibitor benzamil effectively sensitized Reh-MTXR cells to MTX treatment. Moreover, the observed upregulation of ABCG1 in Reh-MTXR cells was not induced by alterations in DNA methylation or histone acetylation. This study provides insight into the mechanistic basis of MTX resistance in ALL and also suggests a potential therapeutic approach for MTX-resistant ALL in the future.

Keywords: ABCG1; ALL; MTX resistance; chemosensitivity; epigenetic modification.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the National Natural Science Foundation of China (82070159 to HL, 81970141 to B-BZ), the Science and Technology Commission of Pudong New Area Foundation (PKJ2020-Y05 to YC, PKJ2023-Y45 to HL), National Key Research and Development Program of China (No. 2021YFA1100800 to B-BZ), Natural Science Foundation of Shanghai (22ZR1440000 to HL, 22ZR1439900 to B-BZ), Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics (20DZ2260900 to B-BZ), Natural Science Foundation of Fujian Province (2023J01184 to HL).