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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 17, 2023
- Source ID
- 10.1182/blood.2022015418
Entities
People
- Abdul Karzai
- Aishwarya Krishnan
- Andrew Dunbar
- Anna Rita Migliaccio
- Anouar Zouak
- Corinne E Hill
- Dongjoo Kim
- Eric Tucker
- Erin McGovern
- Fabrizio Martelli
- Francesca Gobbo
- Giuseppe Sarli
- Jayden Yohai
- Jenna Snyder
- Jing Zhou
- Jonathan J. Chen
- Julie L Yang
- Kavi O'connor
- Keith Bryan Cordner Jr
- Lijuan Xia
- Maria Kleppe
- Min Lu
- Mirko Farina
- Mohamed E. Salama
- Nada Elmansy
- Paola Verachi
- Raajit K. Rampal
- Richard Patrick Koche
- Robert L Bowman
- Ronald Hoffman
- Rong Fan
- Ross L Levine
- Shoron Mowla
- Timothy S Mcconnell
- Wenbin Xiao
- Yang Xiao
- Young C. Park
- Zach Zaroogian
- Zhuo Chen
Organizations
- Icahn School of Medicine at Mount Sinai
- Istituto Superiore di SanitÃ
- Memorial Sloan Kettering Cancer Center
- Regeneron Pharmaceuticals
- University of Bologna
- Yale University