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Targeting KPNB1 suppresses AML cells by inhibiting HMGB2 nuclear import

Oncogene volume 44, pages 1646–1661 (2025)Cite this article

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Abstract

Acute myeloid leukemia (AML) represents the most prevalent malignancy within the hematologic system, characterized by refractory relapses and a scarcity of effective treatment options. Karyopherin subunit beta-1 (KPNB1) is a member of karyopherin β family, mediating the nuclear import of its cargoes. In this study, we found that elevated expression levels of KPNB1 are associated with unfavorable outcomes in patients with AML. The knockdown of KPNB1 resulted in growth inhibition and apoptosis in AML cells. Additionally, pharmacological inhibition of KPNB1 using the specific inhibitor importazole (IPZ) significantly reduced tumor burden and prolonged survival in MLL-AF9-induced AML mice. Notably, the inhibition of KPNB1 by IPZ significantly enhanced the sensitivity of both AML cell lines and patient-derived cells to venetoclax in vitro and in xenograft mice models. At the molecular level, we identified an unrecognized cargo of KPNB1, high mobility group 2 (HMGB2), which plays a crucial role in DNA damage repair. Inhibition of KPNB1 resulted in impaired nuclear import of HMGB2, eventually leading to compromised DNA damage repair in AML cells. Overall, our findings elucidate the essential roles of KPNB1 in AML cells through the HMGB2-DNA damage repair axis and highlight a promising therapeutic target for AML intervention.

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Fig. 1: KPNB1 is highly expressed in AML patient samples and essential for survival and proliferation of AML cells.
Fig. 2: Pharmacologic inhibition of KPNB1 by IPZ suppresses proliferation and induces apoptosis in AML cells.
Fig. 3: Pharmacologic inhibition of KPNB1 by IPZ delays the progression of MLL-AF9-induced AML.
Fig. 4: HMGB2 is a cargo of KPNB1 in AML cells.
Fig. 5: KPNB1 safeguards AML cells via HMGB2-mediated DNA damage repair.
Fig. 6: Inhibition of KPNB1 by IPZ sensitizes leukemia cells to venetoclax.
Fig. 7: Inhibition of KPNB1 by IPZ sensitizes leukemia cells to venetoclax in PDX mice models.

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Data availability

Supplemental Figures and Tables are available in the Supplemental Figures and Tables file. RNA-seq data were deposited in the National Center for Biotechnology Information GEO database and are available under accession number GSE277912. Proteomics are available at PRIDE-Proteomics Identification Database under accession numbers PXD056172. All other data are available in the article and its supplementary materials and are also available upon request from the corresponding author.

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Funding

This work was supported by grants from Chongqing Science Fund for Distinguished Young Scholars (CSTB2022NSCQ-JQX0032), CQMU Program for Youth Innovation in Future Medicine (W0156), Science and Technology Research Program of Chongqing Municipal Education Commission (Grant No. KJQN202400465), and Chongqing Postdoctoral Science Foundation (CSTB2023NSCQ-BHX0144 and 2022CQBSHTB1012).

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Authors and Affiliations

  1. Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China

    Yuxin Xie, Runlong Zhao, Yingjiao Zheng, Yan Li, Feng Wu, Yufei Lei, Hanqing Zeng, Zhe Chen & Yu Hou

  2. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China

    Lei Li

  3. Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China

    Yu Hou

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  1. Yuxin Xie
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  2. Runlong Zhao
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  3. Yingjiao Zheng
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  4. Yan Li
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  6. Yufei Lei
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  8. Hanqing Zeng
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Contributions

Y Hou, Z Chen, and H Zeng conceived the project, analyzed data, and revised the paper. Y Xie performed experiments, analyzed data, and wrote the paper. R Zhao, Y Zheng, Y Li, F Wu, Y Lei, and L Li contributed to the data analysis and paper revision.

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Correspondence to Hanqing Zeng, Zhe Chen or Yu Hou.

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The authors declare no competing interests.

Ethics approval

The authors affirm that all methods were conducted in accordance with the relevant guidelines and regulations. All mice were housed at the Animal Center of Chongqing Medical University, and approval was obtained from the Animal Committee of the Institute of Zoology at Chongqing Medical University (reference number: IACUC-CQMU-2024-0046, “The study on pathogenesis and targeted intervention of acute myeloid leukemia”). Whole BM samples were obtained from AML patients after informed consent of sample use for research. The use of human samples was approved by the Medical Ethics Committees of Chongqing Medical University (reference number: 2024019, “The study on pathogenesis and targeted intervention of acute myeloid leukemia”).

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Xie, Y., Zhao, R., Zheng, Y. et al. Targeting KPNB1 suppresses AML cells by inhibiting HMGB2 nuclear import. Oncogene 44, 1646–1661 (2025). https://doi.org/10.1038/s41388-025-03340-0

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