J Cancer 2022; 13(7):2301-2311. doi:10.7150/jca.66175 This issue

Research Paper

Arsenic trioxide induces proteasome dependent TBLR1-RARα degradation to improve leukemia eradication through cell differentiation enhancement

Yirui Chen1, Manning Li1, Han Wu1, Shijin Yuan2, Yan Xia2, Yingjian Wang2, Ye Peng1, Jianping Lan1✉, Yanzhong Wang2,3✉

1. Cancer center, Department of Hematology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, 58 Shangtang Road, Hangzhou, Zhejiang, China, 310014.
2. Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, China, 310016.
3. Department of Clinical Laboratory, Xiasha Campus, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, Zhejiang, China, 310016.

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Citation:
Chen Y, Li M, Wu H, Yuan S, Xia Y, Wang Y, Peng Y, Lan J, Wang Y. Arsenic trioxide induces proteasome dependent TBLR1-RARα degradation to improve leukemia eradication through cell differentiation enhancement. J Cancer 2022; 13(7):2301-2311. doi:10.7150/jca.66175. Available from https://www.jcancer.org/v13p2301.htm

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Abstract

Graphic abstract

Background: Acute promyelocytic leukemia (APL) mainly harbors PML-RARα fusion gene, which is sensitive to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) treatment. However, APL harboring other RARα fusion genes exhibit different drug sensitivity. Here, we investigated the role and mechanism of TBLR1-RARα, a rare RARα fusion gene, on ATO treatment in leukemia cells.

Methods: By constructing two cell models of leukemia cell line HL-60 and U937 with overexpressed TBLR1-RARα, we detected the cell differentiation in the two cell models after ATO treatment by flow cytometry and Wright staining. Meanwhile, cell viability, colony formation and apoptosis were also determined after ATO treatment.

Results: We found that TBLR1-RARα enhanced ATO-induced apoptosis and cell proliferation inhibition. Besides, TBLR1-RARα also promoted ATO-induced cell differentiation. Furthermore, we found that the mitochondrial caspase pathway was involved in the apoptosis induced by ATO treatment in TBLR1-RARα positive leukemia cells. Moreover, ATO mediated TBLR1-RARα protein degradation via proteasome pathway, which accounts for the transcriptional activation of RARα target gene and is further involved in cell differentiation of TBLR1-RARα positive leukemia cells.

Conclusions: Our study provides evidence that TBLR1-RARα positive APL patients may benefit from ATO treatment, thereby improving the appropriate management in TBLR1-RARα positive APL.

Keywords: Acute promyelocytic leukemia, TBLR1-RARα, Arsenic trioxide, Cell differentiation, Mitochondrial pathway apoptosis, Proteasome-mediated degradation