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Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia

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Abstract

Purpose

Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL.

Methods

NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients’ specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness.

Results

Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival.

Conclusion

Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.

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Data availability

All data and material have been provided in the manuscript and supplement materials.

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Acknowledgements

Profs. Ren-Jiang Lin (City of Hope, California), and Hsin-An Hou (Taiwan University Hospital) provided scientific discussion and reviewed the typescript. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centers funding scheme.

Funding

This work was supported by National Natural Science Foundation of China (81870135, 81470326, U2005204,82000142), Natural Science Foundation of Fujian Province(2020J05049), Joint Funds for the innovation of science and Technology, Fujian province(2021Y9086).

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Author notes

  1. Yanxin Chen, Zhengjun Wu, Lingyan Wang and Minhui Lin contributed equally.

Authors and Affiliations

  1. Fujian Provincial Key Laboratory of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China

    Yanxin Chen, Zhengjun Wu, Lingyan Wang, Minhui Lin, Peifang Jiang, Jingjing Wen, Jiazheng Li, Yunda Hong, Xiaoyun Zheng, Xiaozhu Yang, Jing Zheng, Ting Yang & Jianda Hu

  2. Haematology Research Centre, Department of Immunology and Inflammation, Imperial college London, South Kensington Campus, London, SW7 2AZ, UK

    Robert Peter Gale

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Contributions

JDH. and YXC conceived and designed the experiment; YXC, LYW., JJW., and YDH Did the in vitro experiments and data analysis. ZJW performed animal experiments and data analysis. LYW and PFJ constructed the adriamycin-resistant cells. MHL and YXC collected samples and quantified NCL expression. YXC and analyzed the clinical data. JZL analyzed the data from Target and GEO databases. XYZ, YZY, JZ, and TY provided and analyzed clinical samples and data. YXC, ZJW, and RPG prepared the typescript.

Corresponding authors

Correspondence to Ting Yang or Jianda Hu.

Ethics declarations

Ethics approval and consent to participate

All the experiments were approved by the review board of the Ethics Committee and the Institutional Review Board of Fujian Medical University Union Hospital (2014058). All animal experiments were approved by the Ethics Committee of Institutional Animal Care and Use. BALB/C nude mice and NCG mice experiments were carried out following the guidelines of the animal facility at Fujian Medical University. NSI mice experiments were carried out following the guidelines of the animal facility in the Laboratory Animal Center of the Guangzhou Institutes of Biomedicine and Health (GIBH). All patients gave written informed consent to use their clinical specimens for medical research.

Consent for publication

Written informed consent for publication was obtained from the patients. All authors have agreed to publish this manuscript.

Competing interests

RPG is a consultant to BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Parmaceuticals Inc., and CStone Pharmaceuticals; advisor to Antegene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

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Jianda Hu is the first corresponding author and Ting Yang is the second corresponding author.

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Chen, Y., Wu, Z., Wang, L. et al. Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia. Cell Oncol. 46, 1709–1724 (2023). https://doi.org/10.1007/s13402-023-00837-2

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