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CircZBTB46 predicts poor prognosis and promotes disease progression of myelodysplastic syndromes and acute myeloid leukemia

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Abstract

Circular RNAs (circRNAs) have been recently identified as important regulators of various diseases, especially cancer. However, the roles of circRNAs in hematologic malignancies have been rarely reported. This study aimed to identify a specific circRNA expression profile in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and to evaluate the biological roles of circRNA in MDS and AML for understanding their clinical significance. Reverse transcription-quantitative PCR was performed to validate the expression of circZBTB46. Kruskal–Wallis test, Kaplan–Meier curves, and the Cox regression model were employed to analyze the clinical significance of circZBTB46. Two specific shRNAs as well as an expression lentiviral vector of circZBTB46 were constructed to identify the biological function of circZBTB46. The impact of circZBTB46 on leukemia cell proliferation, cell cycle distribution, and apoptosis was confirmed using cell viability assay and flow cytometry analysis. The expression of circZBTB46 gradually increased in patients with higher-risk MDS and AML, as compared to controls. CircZBTB46 expression was significantly correlated with important clinical parameters of MDS, including WHO classification, absolute neutrophil count (ANC), marrow blast, IPSS karyotype, IPSS/IPSS-R risk groups, and AML transformation. CircZBTB46 expression was also associated with ANC, marrow blast, cytogenetic risk groups, FLT3-ITD mutation, and treatment response in AML patients. Furthermore, circZBTB46 overexpression was significantly correlated with shorter overall survival (OS, P = 0.0342, median survival time 18.5 vs. 45.4 months) and leukemia-free survival (LFS, P = 0.0421) in MDS, also with the shorter OS in AML (P = 0.0293, median survival time 11.6 vs. 16.9 months). Functional studies revealed that silencing circZBTB46 expression significantly inhibited proliferation and induced apoptosis in SKM-1, THP-1, and K562 cell lines, while rescue experiments alleviated the siRNA-mediated growth inhibition and apoptosis in these leukemic cells. The present data suggested the essential oncogenic role of circZBTB46, as a progression and survival indicator in both MDS and AML.

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Data availability

The microarray data of our study were uploaded into the gene expression omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/GSE163386). Further inquiries can be directed to the corresponding author.

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Acknowledgements

We would like to thank the patients and physicians enrolled in this study, who came from eight hospitals in the Shanghai Leukemia Cooperative Group.

Funding

This work was supported by the grant from the National Natural Science Foundation of China (NSFC) [grant number 82000134].

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Authors and Affiliations

  1. Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University, No.85 Wujin Road, Shanghai, China

    Shuang Li & Xianmin Song

  2. Department of Hematology, Huashan Hospital, Fudan University, No.12 Wulumuqi Middle Road, Shanghai, China

    Guangjie Zhao, Wanling Wu, Nianyi Li, Qian Wang, Wei Wang & Xiaoqin Wang

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  1. Shuang Li
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  2. Guangjie Zhao
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  3. Wanling Wu
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  4. Nianyi Li
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  5. Qian Wang
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  6. Wei Wang
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  7. Xianmin Song
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  8. Xiaoqin Wang
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Contributions

XW and XS designed the project. SL and GZ performed the experiments and drafted the manuscript. SL and GZ contributed equally to this study. WW and NL performed some experiments and analyzed the data. WW and QW collected the patient samples. XS and XW revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

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Correspondence to Xianmin Song or Xiaoqin Wang.

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The authors declare that there are no competing interests associated with the manuscript.

Ethics approval and consent to participate

The present study, which involved human samples, obtained approval from the Research Ethics Committee of Huashan Hospital, Fudan University. Each patient provided informed consent for participation.

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Li, S., Zhao, G., Wu, W. et al. CircZBTB46 predicts poor prognosis and promotes disease progression of myelodysplastic syndromes and acute myeloid leukemia. Clin Exp Med 23, 4649–4664 (2023). https://doi.org/10.1007/s10238-023-01243-6

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  • DOI: https://doi.org/10.1007/s10238-023-01243-6

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