By Rob Dillard
December 12, 2023
Megakaryocytes (Mks) derived PF4 play an important role in the progression of myelofibrosis, according to a study that will be presented at the 65th ASH Annual Meeting & Exposition, which is taking place December 9-12 in San Diego, California.
“Previous research has shown that [Mks] play a role in myeloproliferative neoplasm (MPN) pathology by promoting inflammation and extracellular matrix deposition by activated stromal cells. However, the specific factors derived from Mks that contribute to the inflammatory milieu and myelofibrosis progression are not well defined,” the researchers wrote. In this study, they sought to determine which events drive bone marrow (BM) fibrosis via abnormal MK-stromal cross talk.
To conduct their analysis, Alessandro Malara and colleagues induced myelofibrosis in mice via injections of thrombopoietin-mimetic romiplostim (TPOhigh). Then, they isolated and assessed Mks, BM cells, and platelets from TPOhigh and control mice (injected with saline). They also analyzed protein extracts and cytokine levels in the plasma and BM cell-free fluids of treated mice.
To assess fibrosis-related markers, the investigators evaluated the expression of 2 myofibroblasts markers (a-SMA and vimentin), both in mouse embryonic fibroblasts (mEFs) and human BM mesenchymal stromal cells after stimulation with recombinant PF4 using Western blot.
The findings demonstrated that signaling pathways related to cytoskeletal reorganization, cell adhesion, and inflammation were commonly activated in the Mks, platelets, and BM cells of TPOhigh mice versus the saline-injected control mice. Among the differentially expressed proteins, chemokinePF4/Cxcl4 was upregulated exclusively in the proteasomes of the TPOhigh mice. Importantly, the investigators noted that the findings show these mechanisms were interconnected during Mk-mEF cross talk.
“Our findings identify a crucial role of Mk derived PF4 in the fibrosis progression of MPN, providing further support for the potential therapeutic strategy of neutralizing PF4,” the researchers concluded.
Reference
Malara A, Capitanio D, Calledda F, et al. Proteomic screening identifies megakaryocyte derived PF4/Cxcl4 as a critical driver of myelofibrosis. Abstract #1793. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.