Proteomic Analysis Reveals Alterations That Drive Myelofibrosis

Using mass spectrometry-based proteomics, researchers identified chemokine platelet factor 4 (PF4)/Cxcl4 as a driver of myelofibrosis.

The analysis was led by Daniele Capitanio, PhD, of the University of Milan, and published in Leukemia.

Dr. Capitanio and colleagues discovered an increase of PF4 in the plasma and bone marrow (BM) fluids of fibrotic mice. In vitro, high concentrations of thrombopoietin sustained the production and release of PF4 in cultured megakaryocytes. In vivo, ruxolitinib treatment inhibited abnormal PF4 expression.

They also found that PF4 is internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. In conditions with high thrombopoietin concentrations, silencing the Cxcl4 gene mitigated the profibrotic phenotype of stromal cells.

Extensive PF4 uptake by stromal cells and altered GAG deposition were detected in both JAK2^V617F mice treated with romiplostim and the BM biopsies of patients with myeloproliferative neoplasms (MPN). In the romiplostim-treated mice, GAG inhibition improved fibrosis in vivo.

“Our findings highlight the critical role of PF4 in the fibrosis progression of MPN and substantiate the potential therapeutic strategy of neutralizing PF4-GAG interaction,” the researchers concluded.

Reference

Capitanio D, Calledda FR, Abbonante V, et al. Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis. Leukemia. 2024. doi:10.1038/s41375-024-02354-z