Abstract

Polycythemia Vera (PV) is a myeloproliferative neoplasm with increased risk of thrombosis and progression to myelofibrosis. Chronic inflammation is commonly observed in myeloproliferative neoplasms including PV. The inflammatory network includes the extracellular vesicles (EVs), which play a role in cell-cell communication. Recent evidence points to circulating microbial components/microbes as potential players in hemopoiesis regulation. To address the role of EVs in PV, here we investigated phenotype and microbial DNA cargo of circulating EVs through multidimensional analysis. Peripheral blood and feces were collected from PV patients (n=38) and healthy donors (n=30). Circulating megakaryocyte (MK)- and platelet (PLT)-derived EVs were analyzed by flow cytometry. After microbial DNA extraction from feces and isolated EVs, the 16S rDNA V3-V4 region was sequenced. We found that the proportion of circulating MK-derived EVs was significantly decreased in PV patients as compared with the healthy donors. By contrast, the proportion of the PLT-derived EVs was increased. Interestingly, PV was also associated with a microbial DNA signature of the isolated EVs with higher diversity and distinct microbial composition than the healthy counterparts. Of note, increased proportion of isolated lipopolysaccharide-associated EVs has been demonstrated in PV patients. Conversely, the gut microbiome profile failed to identify a distinct layout between PV patients and healthy donors. In conclusion, PV is associated with circulating EVs harbouring abnormal phenotype and dysbiosis signature with a potential role in the (inflammatory) pathogenesis of the disease.

Highlights

  • Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by clonal expansion of the erythrocyte mass

  • Prior reports showed that serum microparticles originating from platelets, erythrocytes, granulocytes, and endothelial cells of PV patients are elevated compared with healthy controls [32]

  • It has been described that patients with MPNs that had the JAK2V617F mutation had significantly higher plasma concentrations of tissue factor–positive microparticles and erythrocyte microparticles [33]

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Summary

Introduction

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm (MPN) characterized by clonal expansion of the erythrocyte mass. Molecular pathogenesis relies on constitutive activation of the JAK-STAT pathway that is responsible for abnormal myeloproliferation and increased production of circulating inflammatory cytokines [1, 2]. All MPNs are associated with an important inflammatory response as demonstrated by the presence of high plasma levels of inflammatory cytokines as well as constitutional symptoms alleviated by anti-inflammatory therapies. These inflammatory cytokines are synthetized by the mutated and non-mutated hematopoietic cells as well as by non-hematopoietic cells such as mesenchymal stromal cells [5,6,7,8]. Inflammation is an important thrombotic risk factor in PV [3, 4, 9]

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