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Inhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm

Author

Listed:
  • Shivam Rai

    (University Hospital Basel, University of Basel)

  • Elodie Grockowiak

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus)

  • Nils Hansen

    (University Hospital Basel, University of Basel)

  • Damien Luque Paz

    (University Hospital Basel, University of Basel)

  • Cedric B. Stoll

    (University Hospital Basel, University of Basel)

  • Hui Hao-Shen

    (University Hospital Basel, University of Basel)

  • Gabriele Mild-Schneider

    (University Hospital Basel, University of Basel)

  • Stefan Dirnhofer

    (University Hospital Basel)

  • Christopher J. Farady

    (Novartis Institutes for BioMedical Research Forum 1)

  • Simón Méndez-Ferrer

    (Wellcome-MRC Cambridge Stem Cell Institute
    University of Cambridge
    Cambridge Biomedical Campus)

  • Radek C. Skoda

    (University Hospital Basel, University of Basel)

Abstract

Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1β serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1β overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1β in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1β in JAK2-V617F mutant mice by anti-IL-1β antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1β with anti-IL-1β antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.

Suggested Citation

  • Shivam Rai & Elodie Grockowiak & Nils Hansen & Damien Luque Paz & Cedric B. Stoll & Hui Hao-Shen & Gabriele Mild-Schneider & Stefan Dirnhofer & Christopher J. Farady & Simón Méndez-Ferrer & Radek C. S, 2022. "Inhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32927-4
    DOI: 10.1038/s41467-022-32927-4
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    References listed on IDEAS

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    1. Lorena Arranz & Abel Sánchez-Aguilera & Daniel Martín-Pérez & Joan Isern & Xavier Langa & Alexandar Tzankov & Pontus Lundberg & Sandra Muntión & Yi-Shiuan Tzeng & Dar-Ming Lai & Jürg Schwaller & Radek, 2014. "Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms," Nature, Nature, vol. 512(7512), pages 78-81, August.
    2. Mohammed Ferdous-Ur Rahman & Yue Yang & Bao T. Le & Avik Dutta & Julia Posyniak & Patrick Faughnan & Mohammad A. Sayem & Nadine S. Aguilera & Golam Mohi, 2022. "Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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