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

Authors
  • Rai, Shivam
  • Grockowiak, Elodie
  • Hansen, Nils
  • Luque Paz, Damien
  • Stoll, Cedric B
  • Hao-Shen, Hui
  • Mild-Schneider, Gabriele
  • Dirnhofer, Stefan
  • Farady, Christopher J
  • Méndez-Ferrer, Simón
  • Skoda, Radek C
Publication Date
Sep 13, 2022
Source
Apollo - University of Cambridge Repository
Keywords
Language
English
License
Green
External links

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.

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