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

The somatic JAK2V617F mutation is found in a majority of patients with myeloproliferative neoplasms (MPN). Chronic inflammation is often associated with MPN, but the role of inflammation in the pathogenesis of MPN remains elusive. Expression of interleukin-1 (IL-1), a key regulator of inflammation, is found elevated in MPN. Here, we show that increased IL-1β enhances myeloid cell expansion and promotes the development of bone marrow (BM) fibrosis in heterozygous Jak2V617F mouse model of MPN. Genetic deletion of IL-1 receptor 1 (IL-1R1) preferentially inhibited the expansion of Jak2 mutant hematopoietic stem/progenitor cells. Furthermore, IL-1R1 deletion or blockade with anti-IL-1R1 antibody significantly reduced leukocytosis and splenomegaly, and markedly inhibited BM fibrosis in homozygous Jak2V617F mutant mice. Collectively, our results suggest that IL-1 signaling plays an important role in progression to BM fibrosis in MPN, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis. RNA-sequencing on sorted LSK and LK cells from heterozygous Jak2V617F knock-in mice treated with vehicle (PBS) and IL-1β. RNA-seq analysis on bone marrow (BM) mesenchymal stromal cells (MSC) stimulated with vehicle (PBS) and IL-1β.

体细胞JAK2V617F突变（somatic JAK2V617F mutation）在绝大多数骨髓增殖性肿瘤（myeloproliferative neoplasms, MPN）患者中均可检出。慢性炎症常与骨髓增殖性肿瘤相伴存在，但炎症在骨髓增殖性肿瘤发病机制中的作用仍有待阐明。作为关键炎症调控因子，白细胞介素-1（interleukin-1, IL-1）的表达水平在骨髓增殖性肿瘤中显著升高。本研究证实，在杂合子Jak2V617F突变骨髓增殖性肿瘤小鼠模型中，白细胞介素-1β（IL-1β）水平升高可促进髓系细胞扩增，并推动骨髓纤维化（bone marrow, BM）的发生与进展。敲除白细胞介素-1受体1（IL-1 receptor 1, IL-1R1）可优先抑制Jak2突变型造血干/祖细胞的扩增。进一步研究显示，在纯合子Jak2V617F突变小鼠中，敲除IL-1R1或使用抗IL-1R1抗体阻断该通路，可显著减轻白细胞增多症与脾肿大，并明显抑制骨髓纤维化的进展。综上，本研究结果提示IL-1信号通路在骨髓增殖性肿瘤进展为骨髓纤维化的过程中发挥重要作用，靶向IL-1R1或可成为治疗骨髓纤维化的有效策略。本研究的数据集包含两类测序分析样本：一是对经赋形剂（磷酸盐缓冲液，PBS）或IL-1β处理的杂合子Jak2V617F敲入小鼠的分选LSK与LK细胞进行RNA测序（RNA-sequencing）；二是对经赋形剂（PBS）或IL-1β刺激的骨髓间充质基质细胞（bone marrow mesenchymal stromal cells, MSC）开展RNA测序分析。