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

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 and Radek C. Skoda ()
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Shivam Rai: University Hospital Basel, University of Basel
Elodie Grockowiak: Wellcome-MRC Cambridge Stem Cell Institute
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
Radek C. Skoda: University Hospital Basel, University of Basel

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32927-4

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