CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis

•MF hematopoietic stem cells aberrantly secrete CXCL8 and exhibit enhanced cell growth/output in response to CXCL8 in vitro.•Genetic deletion or inhibition of Cxcr2 in the hMPLW515L-adoptive transfer model ameliorates fibrosis and improves hematologic parameters. [Display omitted] Proinflammatory 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 are yet to be fully elucidated. Previously, we identified a critical role for combined constitutive JAK/STAT and aberrant NF-κB proinflammatory signaling in MF development. Using single-cell transcriptional and cytokine-secretion studies of primary cells from patients with MF and the human MPLW515L (hMPLW515L) murine model of MF, we extend our previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. Hematopoietic stem/progenitor cells from patients with MF are enriched for a CXCL8/CXCR2 gene signature and display enhanced proliferation and fitness in response to an 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 among patients with MF. Cytokines are known to be proinflammatory messengers in myeloproliferative neoplasms (MPNs) and are suspected to be important in the late stages of these diseases. Using primary human samples, single-cell cytokine profiling, and murine models, Dunbar and colleagues reveal that the CXCL8/CXCR2 cytokine-signaling axis is a key mediator of bone marrow fibrosis in MPN, providing a therapeutically tractable avenue to prevent, or treat, this lethal complication of MPN