A Specific Host/Microbial Signature of Plasma-Derived Extracellular Vesicles Is Associated to Thrombosis and Marrow Fibrosis in Polycythemia Vera

Polycythemia vera (PV) is a myeloproliferative neoplasm with increased risk of thrombosis and progression to myelofibrosis. However, no disease-specific risk factors have been identified so far. Circulating extracellular vesicles (EVs) are mostly of megakaryocyte (MK-EVs) and platelet (PLT-EVs) origin and, along with phosphatidylethanolamine (PE)-EVs, play a role in cancer and thrombosis. Interestingly, circulating microbial components/microbes have been recently indicated as potential modifiers of inflammation and coagulation. Here, we investigated phenotype and microbial DNA cargo of EVs after isolation from the plasma of 38 patients with PV. Increased proportion of MK-EVs and reduced proportion of PLT-EVs identify patients with thrombosis history. Interestingly, EVs from patients with thrombosis history were depleted in Staphylococcus DNA but enriched in DNA from Actinobacteria members as well as Anaerococcus. In addition, patients with thrombosis history had also lower levels of lipopolysaccharide-associated EVs. In regard to fibrosis, along with increased proportion of PE-EVs, the EVs of patients with marrow fibrosis were enriched in DNA from Collinsella and Flavobacterium. Here, we identified a PV-specific host/microbial EV-based signature associated to thrombosis history and marrow fibrosis. These data may contribute to refining PV prognosis and to identifying novel druggable targets.

真性红细胞增多症（Polycythemia vera, PV）是一种骨髓增殖性肿瘤（myeloproliferative neoplasm），患者血栓形成风险升高，且可进展为骨髓纤维化（myelofibrosis）。然而，目前尚未发现该病特异性的风险因素。循环细胞外囊泡（extracellular vesicles, EVs）主要来源于巨核细胞（MK-EVs）与血小板（PLT-EVs），连同磷脂酰乙醇胺（phosphatidylethanolamine, PE）修饰的细胞外囊泡（PE-EVs），在肿瘤发生与血栓形成过程中发挥调控作用。值得注意的是，近期研究证实循环微生物组分或微生物本身可作为炎症与凝血功能的潜在调节因子。本研究针对38例PV患者血浆中分离得到的细胞外囊泡，分析了其表型与微生物DNA载荷特征。结果显示，巨核细胞来源细胞外囊泡（MK-EVs）比例升高、血小板来源细胞外囊泡（PLT-EVs）比例降低，可有效区分存在血栓病史的PV患者。有趣的是，存在血栓病史的患者其细胞外囊泡中葡萄球菌属（Staphylococcus）DNA丰度显著降低，而放线菌门（Actinobacteria）成员及厌氧球菌属（Anaerococcus）的DNA丰度则显著升高。此外，该类患者的脂多糖关联细胞外囊泡（lipopolysaccharide-associated EVs）水平也更低。针对骨髓纤维化亚组，除磷脂酰乙醇胺（PE）修饰的细胞外囊泡（PE-EVs）比例升高外，合并骨髓纤维化的患者其细胞外囊泡中柯林斯菌属（Collinsella）与黄杆菌属（Flavobacterium）的DNA丰度亦显著升高。本研究鉴定出了与PV患者血栓病史及骨髓纤维化相关的、基于宿主与微生物来源细胞外囊泡的PV特异性特征谱。上述研究结果可为优化PV患者的预后评估及发掘全新的可药物靶向治疗靶点提供科学依据。