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Prognostic value and therapeutic targeting of XPO1 in chronic lymphocytic leukemia

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Abstract

Chronic lymphocytic leukemia (CLL) is a subtype of B-cell malignancy with high heterogeneity. XPO1 is highly expressed in many hematological malignancies, which predicts poor prognosis. In the study, we aimed to explore the prognostic role of XPO1 and the therapeutic effect of Selinexor, a selective inhibitor of nuclear export, which targets XPO1. We collected 200 CLL samples in our center to confirm XPO1 mRNA expression and analyzed the correlation between XPO1 expression and prognosis. Then, we decreased XPO1 expression with Selinexor to explore the effect of proliferation inhibition, cell cycle arrest, and apoptosis in CLL cell lines. RNA-Seq was performed to explore potential mechanisms. We analyzed XPO1 expression in a cohort of 150 treatment naive patients and another cohort of 50 relapsed and refractory (R/R) patients and found that XPO1 expression was upregulated in 76% of CLL patients compared with healthy donors. Survival analysis suggested that patients with increased XPO1 expression had inferior treatment-free survival (P = 0.022) and overall survival (P = 0.032). The inhibitor of XPO1, Selinexor, induced apoptosis in primary CLL cells. We showed the effects of Selinexor on proliferation inhibition, cell cycle arrest, and apoptosis in CLL cell lines with JVM3, MEC1, and ibrutinib-resistant (MR) cells via nuclear retention of cargo proteins of IκBα, p65, p50, and FOXO3a. Moreover, downregulation of the NF-κB and FOXO pathways was a common feature of the three CLL cell lines responding to Selinexor, indicating the potential application of XPO1 inhibitor even in the high-risk CLL cells. We identified XPO1 as an unfavorable prognostic factor for CLL patients and provided a rationale for further investigation of the clinically XPO1 targeted therapeutic strategy against CLL.

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The authors declare that all data and materials are available on request.

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Acknowledgements

We would like to acknowledge the patients who volunteered to participate in this study and the Core Facility of the First Affiliated Hospital of Nanjing Medical University for their instructions.

Funding

This work was supported by National Natural Science Foundation of China (81800192, 82100207, 82200210, 82100207), Nature Science Foundation for Youths of Jiangsu Province (BK20210962, BK2021041892, BK2022043464, BK20210962), and Young Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (PY2021026).

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Author notes

  1. Zhangdi Xu and Bihui Pan have contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China

    Zhangdi Xu, Bihui Pan, Yi Miao, Yue Li, Shuchao Qin, Jinhua Liang, Yilin Kong, Xinyu Zhang, Jing Tang, Yi Xia, Huayuan Zhu, Li Wang, Jianyong Li, Jiazhu Wu & Wei Xu

  2. Key Laboratory of Hematology of Nanjing Medical University, Nanjing, 210029, China

    Zhangdi Xu, Bihui Pan, Yi Miao, Yue Li, Shuchao Qin, Jinhua Liang, Yilin Kong, Xinyu Zhang, Jing Tang, Yi Xia, Huayuan Zhu, Li Wang, Jianyong Li, Jiazhu Wu & Wei Xu

  3. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing, 210029, China

    Zhangdi Xu, Bihui Pan, Yi Miao, Yue Li, Shuchao Qin, Jinhua Liang, Yilin Kong, Xinyu Zhang, Jing Tang, Yi Xia, Huayuan Zhu, Li Wang, Jianyong Li, Jiazhu Wu & Wei Xu

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  1. Zhangdi Xu
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Contributions

ZX carried out most of the experiments. BP and JW provided the study design. ZX and BP participated in writing the article and making figures and tables. YL and YX were responsible for analyzing data and interpreting results. Sample collection and clinical data interpretation were completed by YM, SQ, JL, XZ, JT, HZ and LW. JL, JW, and WX provided instructions and revised the paper. Final approval of the manuscript was performed by all authors who contributed to the article.

Corresponding authors

Correspondence to Jiazhu Wu or Wei Xu.

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The study was approved by the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital. And written informed consent was obtained from all patients according to the Declaration of Helsinki.

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Xu, Z., Pan, B., Miao, Y. et al. Prognostic value and therapeutic targeting of XPO1 in chronic lymphocytic leukemia. Clin Exp Med 23, 2651–2662 (2023). https://doi.org/10.1007/s10238-023-01003-6

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