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MULTIPLE MYELOMA, GAMMOPATHIES

Aberrant activation of TRIP13-EZH2 signaling axis promotes stemness and therapy resistance in multiple myeloma

Leukemia volume 37, pages 1576–1579 (2023)Cite this article

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Cells with a stem-like, dormant phenotype, endowed with unlimited self-renewal ability and tumorigenicity are thought to be responsible for post-therapy relapse in various malignancies [1, 2]. Multiple myeloma stem cells (MMSCs) constitute a distinct subpopulation of tumor cells with stemness ability [3, 4]. Thus, elucidating the mechanisms underlying MMSC properties is expected to shed light on the high recurrence rate and drug resistance of multiple myeloma (MM). Thyroid hormone receptor-interacting protein 13 (TRIP13) encodes a highly conserved AAA (ATPases associated with diverse cellular activities) ATP enzyme that contributes to homologous pairing, synapsis, and recombination during meiosis [5, 6]. It is one of the 10 genes that make up the chromosomal instability signature in high-risk MM [7]. Aberrant expression and activation of TRIP13 are associated with poor prognosis of MM patients [8, 9]. However, the biological function of TRIP13 in regulating stemness in MM remains unknown. This study aimed to explore the mechanisms through which TRIP13 maintains MMSC phenotype and its association with bortezomib (BTZ) resistance.

TRIP13 OE promotes myeloma cell growth and drug resistance [8]. However, the relationship between TRIP13 OE, BTZ resistance, and MM stemness remains unknown. To this end, we introduced H929 and RPMI8226 BTZ-resistant cell lines (H929R and RPMI8226R5) to confirm whether BTZ resistance is associated with increased TRIP13 expression and stemness properties. BTZ-resistant cell lines exhibited more and larger spheroids (Fig. S1A), enhanced ALDH1 activity (Fig. S1B), and higher expressions of TRIP13 and iPS/ES genes than the control group (Fig. S1C). This was similar to the pattern of the enhanced stemness characteristics of TRIP13-OE myeloma cells. Importantly, blocking the activity of TRIP13 using DCZ0415 (an inhibitor of TRIP13 enzyme activity) reduced stemness features of ARP1, OCI-MY5, and BTZ-resistant cells (data not shown) . These results suggest that BTZ resistance is closely related to TRIP13-induced stemness in MM.

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Fig. 1: TRIP13 confers stemness properties to multiple myeloma.
Fig. 2: TRIP13 promotes MM stemness and chemoresistance by regulating EZH2 expression.

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Requests for original data may be submitted via e-mail to the corresponding author (shijumei@tongji.edu.cn).

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Acknowledgements

The authors thank the patients and healthy volunteers for their blood donations; The Myeloma Research Group of the Department of Hematology, Shanghai Tenth People’s Hospital for requesting patient consent and assisting with sample collection.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82170200, 81870158, 82070224, 81900207, 82000220, 81971529, and 22077131), Chinese Pharmaceutical Association-Yiling Biopharmaceutical Innovation Project (CPAYLJ201908).

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  1. These authors contributed equally: Li Xu and Yingcong Wang.

Authors and Affiliations

  1. Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Li Xu, Guanli Wang, Shushan Guo, Qilin Feng, Ke Hu, Gege Chen, Xinyan Jia, Hui Zhang, Xuejie Gao, Shuaikang Chang, Dongliang Song, Guang Yang, Jinfeng Zhou & Jumei Shi

  2. Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, China

    Yingcong Wang, Dandan Yu, Gege Chen, Yumeng Lu, Huaping Wang, Xiaosong Wu & Huabin Zhu

  3. CAS Key Laboratory of Receptor Research; State Key Laboratory of Drug Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Bo Li, Zhijian Xu & Weiliang Zhu

  4. Myeloma Center, Winthrop P. Rockefeller Cancer Institute, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Fenghuang Zhan

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Contributions

JS conceived and designed the research; JS, LX, YW, and WZ organized, analyzed and interpreted the data; LX, YW, GW, SG, DY, QF, KH, GC, XJ, HZ (Zhang), XG, HZ (Zhu) and JZ performed the experiments; SC, YL and HW provided key clinical specimens; XW, DS and GY performed the statistical analysis; JS and LX drafted the manuscript; BL, ZX, WZ, and FZ edited the manuscript.

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Correspondence to Jumei Shi.

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Xu, L., Wang, Y., Wang, G. et al. Aberrant activation of TRIP13-EZH2 signaling axis promotes stemness and therapy resistance in multiple myeloma. Leukemia 37, 1576–1579 (2023). https://doi.org/10.1038/s41375-023-01925-w

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