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MULTIPLE MYELOMA, GAMMOPATHIES

VDAC2 primes myeloma cells for BAK-dependent apoptosis and represents a novel therapeutic target

Leukemia volume 39, pages 995–1000 (2025)Cite this article

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BAX and BAK, key executors of apoptosis from the BCL2 family [1], are also regulated by non-BCL2 family proteins, such as the mitochondrial channel VDAC2 [2]. Although well-recognized for its role in metabolite and ion flux [3], VDAC2 has drawn particular attention for its involvement in the regulation of apoptosis. VDAC2 was reported as being necessary for efficient BAX-dependent apoptosis [4], while inhibiting BAK apoptotic function [5]. BAX, but not BAK, is a well-known p53 target gene, and p53-mediated regulation of BAX is required for an optimal response to BH3-mimetics targeting BCL2 or MCL1 [6, 7]. In p53-deficient myeloma cells with low BAX expression, apoptosis is expected to rely on BAK expression and regulation. These data prompted us to investigate whether targeting VDAC2 would overcome the mitochondrial resistance of p53-deficient cells.

To investigate how VDAC2 influences mitochondrial apoptosis in multiple myeloma (MM), we performed transient silencing of VDAC2 in TP53-deficient human myeloma cell lines (HMCLs). Additionally, we evaluated the pharmacological targeting of VDAC2 in both MM cell lines and primary MM patient cells.

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Fig. 1: Transient inhibition of VDAC2 enhances mitochondrial priming and sensitivity to BH3-mimetics.
Fig. 2: The VDAC2 modulator Efsevin increases mitochondrial priming and sensitivity to BH3-mimetics in MM cell lines and primary cells.

Data availability

RNA-sequencing datasets are publicly available [8]. Data that support the findings of this study are included in this published article and in its supplementary information files and are available from the corresponding author on reasonable request

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Acknowledgements

The authors acknowledge the Cytocell-Flow Cytometry and FACS core facility (Structure Fédérative de Recherche (SFR) Bonamy, BioCore, Inserm UMS 016, CNRS UAR 3556, Nantes, France), member of the Scientific Interest Group Biogenouest and the labex IGO-program supported by the French National Research Agency (n°ANR-11-LABX-0016-01) for its technical support. The authors thank the Genomics Core Facility GenoA, member of Biogenouest and France Genomique, and the Bioinformatics Core Facility BiRD, member of Biogenouest and Institut Français de Bioinformatique (ANR-11-INBS-0013) for the use of their resources and their technical support.

Funding

This work was supported by grants from Ligue Contre le Cancer, Comité de Loire-Atlantique (CD44) and Vendée (CD85), Action Cancer 44 and INCA (INCa-DGOS-INSERM_12558, INCa-DGOS-INSERM-ITMO Cancer_18011). OC was supported by grants from HEMA-NexT (Chaire NexT to CT; ANR-16-IDEX-0007) and Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFRMG).

Author information

Authors and Affiliations

  1. Nantes Université, CHU Nantes, CNRS, INSERM, CRCI2NA, Université d’Angers, Nantes, France

    Ophélie Champion, Sophie Maïga, Chloé Antier, Christelle Dousset, Agnès Moreau-Aubry, Céline Bellanger, François Guillonneau, Géraldine Descamps, Philippe Moreau, David Chiron, Catherine Pellat-Deceunynck, Cyrille Touzeau & Patricia Gomez-Bougie

  2. SIRIC-ILIAD (Imaging and Longitudinal Investigations to Ameliorate Decision-making), Nantes, France

    Ophélie Champion, Sophie Maïga, Christelle Dousset, Agnès Moreau-Aubry, Céline Bellanger, François Guillonneau, Géraldine Descamps, Philippe Moreau, David Chiron, Catherine Pellat-Deceunynck, Cyrille Touzeau & Patricia Gomez-Bougie

  3. Prot’ICO Proteomics Facility, Institut de Cancérologie de l’Ouest (ICO), Angers, France

    François Guillonneau

  4. Department of Chemistry and Biochemistry, University of California—Los Angeles, Los Angeles, CA, USA

    Jose Antonio Moreno & Ohyun Kwon

  5. Hematology Department, CHU Nantes, Nantes, France

    Nicoletta Libera Lilli

Authors
  1. Ophélie Champion
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  2. Sophie Maïga
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Contributions

OC participated in the design of the study, performed experiments, derived CRISPR/Cas9 clones, analyzed the data, and participated in the writing of the manuscript; AMA and CD designed CRISPR/Cas9 strategy and profiled CRISPR/Cas9 BAK1 and BAX cells; SM managed the patient cohort and performed experiments; CB performed bioinformatic analysis and analyzed 3′SRP sequencing; FG participated in the proofreading of the manuscript; CA and GD performed experiments. JAM and OK synthetized Efsevin; NLL managed the patient cohort; PM managed the patient cohort, CT participated in the design of the study and managed the patient cohort; DC and CPD participated in the design of the study, in the writing and revision of the manuscript; PGB designed the study, performed experiments, analyzed the results and wrote the manuscript.

Corresponding authors

Correspondence to Catherine Pellat-Deceunynck or Patricia Gomez-Bougie.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by the University Hospital of Nantes (MYRACLE study; NTC03807128) [14]. The patients provided their written informed consent to participate in this study. All methods used in this study were performed in accordance with the relevant guidelines and regulations.

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Champion, O., Maïga, S., Antier, C. et al. VDAC2 primes myeloma cells for BAK-dependent apoptosis and represents a novel therapeutic target. Leukemia 39, 995–1000 (2025). https://doi.org/10.1038/s41375-025-02523-8

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