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Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199

Acta Pharmacologica Sinica volume 45, pages 180–192 (2024)Cite this article

Abstract

Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.

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Fig. 1: Aberrant expression of CYTH1 in AML is associated with poor prognosis.
Fig. 2: CYTH1 is required for AML adhesion and migration in vitro.
Fig. 3: CYTH1 is required for AML homing and engraftment in vivo.
Fig. 4: SencinH3 attenuates AML cell growth by inhibiting adhesion and survival programs.
Fig. 5: SecinH3 inhibits the growth of AML xenograft tumors.
Fig. 6: SecinH3 sensitizes AML cells to ABT-199.
Fig. 7: SecinH3 overcomes resistance to ABT-199 by modulating MCL1 expression.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81974221, 81974009, 81470330, and 81272624) and the Natural Science Foundation of Henan (232300421280).

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Author notes

  1. These authors contributed equally: Wen-xiang Ren, Hao Guo.

Authors and Affiliations

  1. Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Wen-xiang Ren, Si-yi Chen, Yao-ying Long, Liu-yue Xu, Di Wu, Jiao Qu, Bian-lei Yang, Hong-pei Xu, He Li, Ya-li Yu, An-yuan Zhang, Shan Wang & Zhi-chao Chen

  2. Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Hao Guo & Yi-cheng Zhang

  3. Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450000, China

    Hao Guo & Ke-shu Zhou

  4. Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Sheng-yan Lin

  5. Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yu-lin Cao & Qiu-bai Li

  6. Hubei Engineering Research Center for Application of Extracellular Vesicles, Hubei University of Science and Technology, Xianning, 437100, China

    Qiu-bai Li

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  1. Wen-xiang Ren
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Contributions

QBL and ZCC conceived and designed the study. ZCC and KSZ supervised the study. WXR and HG performed most of the experiments. SYL, SYC, YYL, LYX, DW, YLC, JQ, BLY, HPX, HL, YLY, AYZ, SW, and YCZ helped with data analysis and manuscript revision. HG wrote the manuscript. All of the authors have contributed to this work.

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Correspondence to Ke-shu Zhou, Zhi-chao Chen or Qiu-bai Li.

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Ren, Wx., Guo, H., Lin, Sy. et al. Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199. Acta Pharmacol Sin 45, 180–192 (2024). https://doi.org/10.1038/s41401-023-01142-2

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