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

Shivam RaiElodie GrockowiakNils HansenDamien Luque PazCedric B StollHui Hao-ShenGabriele Mild-SchneiderStefan DirnhoferChristopher J FaradySimón Méndez-FerrerRadek C Skoda
Published in: Nature communications (2022)
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.
Keyphrases
  • stem cells
  • induced apoptosis
  • mouse model
  • bone marrow
  • cell cycle arrest
  • peripheral blood
  • cell proliferation
  • mesenchymal stem cells
  • cell death
  • wild type
  • metabolic syndrome
  • transcription factor