炎性信号是人类癌症的标志性特征，包括骨髓增生性肿瘤（MPNs），尤其是骨髓纤维化（MF）。失调的炎性信号有助于MF的纤维化进展；然而，致病性MPN细胞激活的单个细胞因子介体以促进胶原合成性纤维化和疾病演变尚未完全阐明。我们之前确定了在骨髓纤维化发展中联合构成的JAK / STAT和异常NF-kB炎性信号的关键作用。利用MF患者原代细胞和骨髓纤维化hMPLW515L小鼠模型的单细胞转录和细胞因子分泌研究，我们扩展了以前的工作，并阐明了CXCL8 / CXCR2信号在MF发病机制和骨髓纤维化进展中的作用。MF患者造血干/祖细胞富含CXCL8 / CXCR2基因签名，并在体外对CXCL8配体的反应中表现出增强的增殖和适应性。在hMPLW515L移植模型中Cxcr2的基因缺失消除了纤维化并延长了总体生存期，CXCR1 / 2通路的药物抑制改善了血液学参数，减轻了骨髓纤维化，并与JAK抑制剂疗法协同作用。我们的机制洞察为治疗MF患者的CXCL8 / CXCR2途径提供了理论基础。版权所有©2023年美国血液学学会。

Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-kB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and the hMPLW515L murine model of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients.Copyright © 2023 American Society of Hematology.