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

Abstract

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 two separate murine models 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 in a CXCL8/CXCR2 gene signature and display dose- dependent 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 at risk for continued fibrotic progression.

Integrated Single-Cell Genotyping and Chromatin Accessibility ChartsJAK2V617FHuman Hematopoietic Differentiation

“…Inflammatory disruption of the bone marrow microenvironment has been extensively documented in myelofibrosis 19–21,39,56–59 . Indeed, secretion of inflammatory cytokines is a central feature of MPN pathophysiology and has been shown to provide a supportive niche for the expansion of mutant clones in various disease states, including MPNs and clonal hematopoiesis 33,60–63 .…”

“…Inflammatory disruption of the bone marrow microenvironment has been extensively documented in myelofibrosis [19][20][21]39,[56][57][58][59] .…”

IL-13/IL-4 signaling contributes to fibrotic progression of the myeloproliferative neoplasms

“…Together, our data demonstrate that IL-13 is involved in disease progression in MF and that inhibition of the IL-13/IL-4 signaling pathway might serve as a novel therapeutic target to treat MF.Recent studies have highlighted the role of individual inflammatory cytokines in the fibrotic progression of MF. [3][4][5][6] Although JAK inhibitors reduce the levels of certain circulating cytokines while improving clinical symptoms and reducing splenomegaly in patients with MF, the effect is relatively short lived. Prolonged treatment has a modest effect in cytokine levels with limited changes in the malignant clones or the degree of BM fibrosis.…”