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NOTCH1 inhibition prevents GvHD and maintains GvL effect in murine models

Bone Marrow Transplantation volume 56, pages 2019–2023 (2021)Cite this article

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Current strategies to control GvHD also decreases Graft-versus-Leukemia (GvL) efficiency, leading to increased rates of relapse [1]. Therefore, new approaches are needed to prevent GvHD while retaining GvL activity.

NOTCH signaling plays a crucial role in regulating alloimmune T cell responses during GvHD and its inhibition strongly decreases GvHD severity and mortality [2,3,4,5], thus making NOTCH a therapeutic target for GVHD treatment [6]. We have recently reported the anti-NOTCH activity of the calcium channel modulator Bepridil in NOTCH1-expressing Chronic Lymphocytic Leukemia patients [7,8,9,10]. In the present study, we report Bepridil as a new drug that prevents GvHD while maintaining GvL effects through NOTCH1 inhibition.

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Fig. 1: Effects of Bepridil on GvHD pathogenesis in vitro and on GvHD and GvL reaction in xenogeneic and allogeneic mouse model.

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Acknowledgements

This work was supported by the Associazione Italiana contro le Leucemie-Linfomi e Mieloma (AIL), L’Aquila Section, Italy. This research was funded by Associazione Italiana per la Ricerca sul Cancro (AIRC) (MFAG 2015 - ID.17442 and IG 2018 – ID. 21352 to PS), FIRC-AIRC (Three-years fellowship “Filomena Todini” - ID. 23928 to CR), Italian Ministry of Education, University and Research (MIUR) (Scientific Independence of Young Researchers Project - ID. RBSI14GPBL to PS), Italian Ministry of Health (Ricerca Finalizzata, RF-2016-02364383 to MDI), Gilead Fellowship Program 2016 (to PS).

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Author notes

  1. These authors contributed equally: Stefano Baldoni, Loredana Ruggeri

  2. These authors jointly supervised this work: Paolo Sportoletti, Mauro Di Ianni

Authors and Affiliations

  1. Department of Medicine and Sciences of Aging, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy

    Stefano Baldoni, Francesco Guardalupi, Francesca Ulbar, Bianca Fabi, Carlo Sorrentino & Mauro Di Ianni

  2. Institute of Hematology, Centro di Ricerche Emato-Oncologiche (CREO), University of Perugia, Perugia, Italy

    Stefano Baldoni, Loredana Ruggeri, Beatrice Del Papa, Daniele Sorcini, Andrea Marra, Erica Dorillo, Arianna Stella, Rosaria Sola, Sara Ciardelli, Filomena De Falco, Chiara Rompietti, Francesco Maria Adamo, Antonio Pierini & Paolo Sportoletti

  3. Department of Oncology and Hematology, Ospedale Civile “Santo Spirito”, ASL Pescara, Pescara, Italy

    Raffaella Giancola & Mauro Di Ianni

  4. Department of Medicine and Surgery, University of Perugia, Perugia, Italy

    Emanuela Rosati

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  1. Stefano Baldoni
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Contributions

MDI, LR and PS designed the research study. SB, LR, BDP, DS, FG, ED, FU, AM, AS, RG, BF, RS, SC, FDF, CR, and FMA performed the research. MDI, CS, SB, BDP, PS, AP and LR analyzed the data. PS, RG and ER contributed essential reagents or tools. MDI and CS wrote the paper. All authors approved the final version of the paper.

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Correspondence to Mauro Di Ianni.

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Baldoni, S., Ruggeri, L., Del Papa, B. et al. NOTCH1 inhibition prevents GvHD and maintains GvL effect in murine models. Bone Marrow Transplant 56, 2019–2023 (2021). https://doi.org/10.1038/s41409-021-01297-8

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