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

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.

Inflammasomes and Atherosclerosis: a Mixed Picture

“…Genetic suppression of inflammasomes or IL-1β inhibition improved features of plaque instability. IL-1β inhibition has also recently been shown to improve features of myeloproliferative neoplasm in Jak2 VF mice 95,96 suggesting that this therapy could have multiple benefits in this setting. In addition, Jak2 VF CH may increase aortic aneurysm formation in mice and possibly humans, reflecting increased inflammatory resident-like macrophages in the aortic adventitia.…”

Biological drivers of clinical phenotype in myelofibrosis

“…al. which, in addition, demonstrated that serum IL-1β was derived from JAK2 V617 -mutant HSPC while HSPC IL-1 receptor expression and serum cytokine concentration directly correlated with JAK2 V617F mutant allele fraction [ 85 ]. Moreover, antibody neutralization of IL-1β in a JAK2 V617 -mutant murine model reduced myelofibrosis and osteosclerosis, which was additive to the effects of ruxolitinib, suggesting that strategies that effectively mitigate IL-1 receptor signaling could be disease modifying.…”

JAK2 V617F allele burden in polycythemia vera: burden of proof

“… 65 The study of JAK2 V617F pathophysiology has yielded many new candidates to target clonal expansion in PV. Therapies that upregulate hepcidin, 90 suppress key inflammatory signaling pathways, 26 , 91 , 92 activate p53, 93 , 94 inhibit HIF, 95 target DNA repair pathways, 30 , 96 or facilitate JAK2 V617F stem cell extinction 97 , 98 are exciting developments for PV and will complement JAK2 inhibitor and interferon alfa–based therapies. Our clinical and research goals should be to incorporate these new targets in the treatment of PV, to use the knowledge of JAK2 V617F VAF to better prognosticate and monitor clonal dynamics, and to aspire to provide reliable, safe, and timely clonal suppression ( Table 5 ).…”

“…JAK2 V617F -mutant HSCs elaborate excess cytokines and reactive oxygen species, which alter the bone marrow niche, reinforce the growth advantage of the clonal cells, and drive genomic instability, myelofibrosis, and osteosclerosis. 14 , 25 , 26 , 27 , 28 , 29 , 30 , 31 Mechanistically, excessive JAK2 signaling in the HSC setting results in a pseudohypoxia state owing to hypoxia-inducible factor (HIF) stabilization by reactive oxygen species. Increased HIF leads to a switch from aerobic metabolism to glycolysis and enhances HSC self-renewal via the downregulation of LKB1/ STK11 .…”