Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm

Mohammed Ferdous-Ur Rahman, Yue Yang, Bao T. Le, Avik Dutta, Julia Posyniak, Patrick Faughnan, Mohammad A. Sayem, Nadine S. Aguilera and Golam Mohi ()
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Mohammed Ferdous-Ur Rahman: University of Virginia School of Medicine
Yue Yang: University of Virginia School of Medicine
Bao T. Le: University of Virginia School of Medicine
Avik Dutta: University of Virginia School of Medicine
Julia Posyniak: University of Virginia School of Medicine
Patrick Faughnan: University of Virginia School of Medicine
Mohammad A. Sayem: University of Virginia School of Medicine
Nadine S. Aguilera: University of Virginia School of Medicine
Golam Mohi: University of Virginia School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Chronic inflammation is frequently associated with myeloproliferative neoplasms (MPN), but the role of inflammation in the pathogenesis of MPN remains unclear. Expression of the proinflammatory cytokine interleukin-1 (IL-1) is elevated in patients with MPN as well as in Jak2V617F knock-in mice. Here, we show that genetic deletion of IL-1 receptor 1 (IL-1R1) normalizes peripheral blood counts, reduces splenomegaly and ameliorates bone marrow fibrosis in homozygous Jak2V617F mouse model of myelofibrosis. Deletion of IL-1R1 also significantly reduces Jak2V617F mutant hematopoietic stem/progenitor cells. Exogenous administration of IL-1β enhances myeloid cell expansion and accelerates the development of bone marrow fibrosis in heterozygous Jak2V617F mice. Furthermore, treatment with anti-IL-1R1 antibodies significantly reduces leukocytosis and splenomegaly, and ameliorates bone marrow fibrosis in homozygous Jak2V617F mice. Collectively, these results suggest that IL-1 signaling plays a pathogenic role in MPN disease progression, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.

Date: 2022
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DOI: 10.1038/s41467-022-32928-3

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