CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis.
| Publication Type | Academic Article |
| Authors | Dunbar A, Kim D, Lu M, Farina M, Bowman R, Yang J, 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, Yohai J, Tucker E, Chen J, Zhou J, McConnell T, Migliaccio A, Koche R, Rampal R, Fan R, Levine R, Hoffman R |
| Journal | Blood |
| Volume | 141 |
| Issue | 20 |
| Pagination | 2508-2519 |
| Date Published | 05/18/2023 |
| ISSN | 1528-0020 |
| Keywords | Primary Myelofibrosis, Myeloproliferative Disorders, Neoplasms |
| 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. |
| DOI | 10.1182/blood.2022015418 |
| PubMed ID | 36800567 |
| PubMed Central ID | PMC10273167 |