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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Rai, Shivam 
Grockowiak, Elodie 
Hansen, Nils 
Luque Paz, Damien 
Stoll, Cedric B 

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.

Description

Keywords

Animals, Interleukin-1beta, Janus Kinase 2, Mice, Mice, Knockout, Myeloproliferative Disorders, Neoplasms, Nitriles, Osteosclerosis, Primary Myelofibrosis, Pyrazoles, Pyrimidines

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (C61367/A26670)
European Research Council (648765)
MRC (MR/V005421/1)
Medical Research Council (MC_PC_17230)