CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis Journal Article
| Authors: | Dunbar, A. J.; Kim, D.; Lu, M.; Farina, M.; Bowman, R. L.; Yang, J. L.; Park, Y.; Karzai, A.; Xiao, W.; Zaroogian, Z.; O'Connor, K.; Mowla, S.; Gobbo, F.; Verachi, P.; Martelli, F.; Sarli, G.; Xia, L.; Elmansy, N.; Kleppe, M.; Chen, Z.; Xiao, Y.; McGovern, E.; Snyder, J.; Krishnan, A.; Hill, C.; Cordner, K.; Zouak, A.; Salama, M. E.; Yohai, J.; Tucker, E.; Chen, J.; Zhou, J.; McConnell, T.; Migliaccio, A. R.; Koche, R.; Rampal, R.; Fan, R.; Levine, R. L.; Hoffman, R. |
| Article Title: | CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis |
| Abstract: | 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. © 2023 The American Society of Hematology |
| Keywords: | signal transduction; vasculotropin; adult; controlled study; myeloproliferative disorders; myelofibrosis; overall survival; gene deletion; genetics; myeloproliferative disorder; janus kinase 2; janus kinase inhibitor; myeloid metaplasia; primary myelofibrosis; nonhuman; alpha interferon; neoplasm; neoplasms; animal cell; mouse; animal; metabolism; animals; mice; cd34 antigen; gene expression; gene expression profiling; interleukin 10; interleukin 8; animal experiment; animal model; pathology; toll like receptor 4; cytokine; cytokines; gamma interferon; chromatin; janus kinase; interleukin 6; adoptive transfer; innate immunity; hematopoietic stem cell; cytokine release; cxcl2 chemokine; leukocytosis; disease exacerbation; cxcl1 chemokine; tumor necrosis factor; rna sequence; kruppel like factor 4; transcription initiation site; stat protein; beta actin; calgranulin a; complication; reticulin; rantes; cxcl3 chemokine; internal ribosome entry site; protein c jun; calgranulin b; chemokine receptor cxcr2; leukocyte activation; high throughput sequencing; ruxolitinib; protein fos; transcription factor fosb; humans; human; male; female; article; methylcellulose; chemokine receptor cxcr1; differential expression analysis; betweenness centrality; jak-stat signaling; single cell rna seq; ladarixin; reparixin |
| Journal Title: | Blood |
| Volume: | 141 |
| Issue: | 20 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2023-05-18 |
| Start Page: | 2508 |
| End Page: | 2519 |
| Language: | English |
| DOI: | 10.1182/blood.2022015418 |
| PUBMED: | 36800567 |
| PROVIDER: | scopus |
| PMCID: | PMC10273167 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Ross L. Levine -- Source: Scopus |
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