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LYMPHOMA

First-in-class inhibitor of HSP110 blocks BCR activation through SYK phosphorylation in diffuse large B-cell lymphoma

Leukemia volume 38, pages 1742–1750 (2024) Cite this article

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Abstract

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is driven by aberrant activation of the B-cell receptor (BCR) and the TLR/MyD88 signaling pathways. The heat-shock protein HSP110 is a candidate for their regulation as it stabilizes MyD88. However, its role in overall BCR signaling remains unknown. Here, we used first-in-class HSP110 inhibitors to address this question. HSP110 inhibitors decreased the survival of several ABC-DLBCL cell lines in vitro and in vivo, and reduced the phosphorylation of BCR signaling kinases, including BTK and SYK. We identified an interaction between HSP110 and SYK and demonstrated that HSP110 promotes SYK phosphorylation. Finally, the combination of the HSP110 inhibitor with the PI3K inhibitor copanlisib decreases SYK/BTK and AKT phosphorylation synergistically, leading to suppression of tumor growth in cell line xenografts and strong reduction in patient-derived xenografts. In conclusion, by regulating the BCR/TLR signaling pathway, HSP110 inhibitors are potential drug candidates for ABC-DLBCL patients.

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Fig. 1: HSP110-specific inhibitors reduce DLBCL growth in vitro and in vivo.
The alternative text for this image may have been generated using AI.
Fig. 2: HSP110-specific inhibitors reduce NFκB and BCR signaling pathways.
The alternative text for this image may have been generated using AI.
Fig. 3: HSP110 is a chaperone for SYK and promotes its phosphorylation.
The alternative text for this image may have been generated using AI.
Fig. 4: HSP110 and SYK interaction in DLBCL biopsies.
The alternative text for this image may have been generated using AI.
Fig. 5: HSP110 inhibitor and copanlisib synergize to decrease DLBCL cell survival.
The alternative text for this image may have been generated using AI.

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Data availability

Full materials, methods and data may be shared after request to the corresponding author by e-mail gaetan.jego@u-bourogne.fr.

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Acknowledgements

This work was supported by grants from the Ligue Nationale Contre le Cancer EL2023 LNCC/CaG (GJ and CG), from the Fondation ARC pour la recherche sur le Cancer (GJ), the French National Research Agency (ANR) under the program “Investissements d’Avenir” with reference ANR-11-LABX-0021 (LabEX LipSTIC), ANR-11-LABX-0051 (Labex GR-Ex) and ANR-15-IDE-0003 (I-SITE-BFC), the Conseil Regional de Bourgogne, We also thank the FEDER for their support. This work was also possible with help from Flow Cytometry Core Facility/Inserm UMR1231, at the University of Burgundy.

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Authors and Affiliations

  1. INSERM, UMR1231, Université de Bourgogne, 21078, Dijon, France

    Vincent Cabaud Gibouin, Manon Durand, Christophe Boudesco, François Hermetet, Mayssa Abdelwahed, Carmen Garrido & Gaëtan Jego

  2. Equipe Labellisée « Ligue Nationale Contre le Cancer », Paris, France

    Vincent Cabaud Gibouin, Manon Durand, Christophe Boudesco, François Hermetet, Mayssa Abdelwahed, Carmen Garrido & Gaëtan Jego

  3. Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic

    Kristyna Nozickova & Pavel Klener

  4. Service de Biopathologie, Centre Léon Bérard, Lyon, France

    Catherine Chassagne-Clement

  5. Centre Georges François Leclerc, 21000, Dijon, France

    Carmen Garrido

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Contributions

VCG, MD, CB, FH, KN, PK and GJ designed the study and experiments; VCG, MD, CB, FH, KN, and MA performed the experiments; CCC and CG provided samples and expertise; VCG, MD, CB, FH, CCC, MA, PK, CG, GJ analyzed the experiments; GJ directed the work.

Corresponding author

Correspondence to Gaëtan Jego.

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Research using human material was done in accordance with the Declaration of Helsinki and was approved by Centre Leon Berard ethics committee, Lyon, France (reference AC-2019-3426). All Human participants gave informed consent.

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Gibouin, V.C., Durand, M., Boudesco, C. et al. First-in-class inhibitor of HSP110 blocks BCR activation through SYK phosphorylation in diffuse large B-cell lymphoma. Leukemia 38, 1742–1750 (2024). https://doi.org/10.1038/s41375-024-02302-x

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