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Background <p>Myelofibrosis (MF) is a rare and severe myeloproliferative neoplasm characterized by bone marrow fibrosis, cytopenia, extramedullary hematopoiesis, and systemic inflammation. The tumor microenvironment (TME) plays a crucial role in MF pathogenesis by promoting fibrotic remodeling and supporting malignant clone survival. Among the key mediators of intercellular communication within the TME are extracellular vesicles (EVs), which transport bioactive molecules such as proteins, lipids, and nucleic acids. EVs derived from both malignant and stromal cells might contribute to disease progression and niche remodeling in MF. However, their role in MF TME has still to be defined.</p> Methods <p>EVs were isolated from the platelet-poor plasma of MF patients and age- and sex-matched controls using size-exclusion chromatography. EVs were then characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting for canonical markers, following with the surface protein profiling using bead-based flow cytometry, and lipidomic profiling by liquid chromatography-mass spectrometry. Functional assays assessed the impact of EVs on α-smooth muscle actin (α-SMA) expression in Transforming Growth Factor (TGF)-β–stimulated fibroblasts.</p> Results <p>EVs from MF patients displayed typical EV features (CD9, TSG101, and ALIX positivity) and showed a significant increase in median size compared with control counterparts, suggesting altered vesicle biogenesis. Lipidomic analysis identified 136 species across 12 lipid classes, revealing a distinct MF-specific lipid signature characterized by reduced sphingomyelin levels and increased diacylglycerol, ether-linked phosphatidylcholine, and phosphatidylethanolamine species, as well as enhanced acyl chain unsaturation, indicative of membrane remodeling under inflammatory stress. Surface profiling analysis revealed that MF-derived EVs exhibited a selective depletion of the endothelial marker CD146. Functionally, control-derived EVs significantly suppressed α-SMA expression in TGF-β–stimulated fibroblasts, whereas MF-derived EVs failed to exert this effect, suggesting a loss of regulatory function.</p> Conclusion <p>The integrated biophysical, molecular, and functional characterization of circulating EVs in MF revealed a distinct signature marked by enlarged vesicle size, altered lipid and protein composition, and reduced ability to counteract a fibrosis-related phenotype. These findings support a potential role for circulating EVs in promoting marrow fibrosis and highlight their promise as a liquid biopsy approach for identifying biomarkers and potential therapeutic targets in MF.</p> Graphical Abstract <p></p>

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Multi-parametric profiling of plasma-derived extracellular vesicles reveals a disease-associated molecular signature supporting a liquid biopsy approach in myelofibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Ghazal Narimanfar,
  • Husam B. R. Alabed,
  • Alessia Brancolini,
  • Roberto Maria Pellegrino,
  • Martina Barone,
  • Claudia Venturi,
  • Hillary Catellani,
  • Giovanni Torsello,
  • Luca Pestarino,
  • Andrea Cavalli,
  • Alessandra D’Addio,
  • Alessia Tieghi,
  • Regina Grillari-Voglauer,
  • Francesca Palandri,
  • Lucia Catani

摘要

Background

Myelofibrosis (MF) is a rare and severe myeloproliferative neoplasm characterized by bone marrow fibrosis, cytopenia, extramedullary hematopoiesis, and systemic inflammation. The tumor microenvironment (TME) plays a crucial role in MF pathogenesis by promoting fibrotic remodeling and supporting malignant clone survival. Among the key mediators of intercellular communication within the TME are extracellular vesicles (EVs), which transport bioactive molecules such as proteins, lipids, and nucleic acids. EVs derived from both malignant and stromal cells might contribute to disease progression and niche remodeling in MF. However, their role in MF TME has still to be defined.

Methods

EVs were isolated from the platelet-poor plasma of MF patients and age- and sex-matched controls using size-exclusion chromatography. EVs were then characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting for canonical markers, following with the surface protein profiling using bead-based flow cytometry, and lipidomic profiling by liquid chromatography-mass spectrometry. Functional assays assessed the impact of EVs on α-smooth muscle actin (α-SMA) expression in Transforming Growth Factor (TGF)-β–stimulated fibroblasts.

Results

EVs from MF patients displayed typical EV features (CD9, TSG101, and ALIX positivity) and showed a significant increase in median size compared with control counterparts, suggesting altered vesicle biogenesis. Lipidomic analysis identified 136 species across 12 lipid classes, revealing a distinct MF-specific lipid signature characterized by reduced sphingomyelin levels and increased diacylglycerol, ether-linked phosphatidylcholine, and phosphatidylethanolamine species, as well as enhanced acyl chain unsaturation, indicative of membrane remodeling under inflammatory stress. Surface profiling analysis revealed that MF-derived EVs exhibited a selective depletion of the endothelial marker CD146. Functionally, control-derived EVs significantly suppressed α-SMA expression in TGF-β–stimulated fibroblasts, whereas MF-derived EVs failed to exert this effect, suggesting a loss of regulatory function.

Conclusion

The integrated biophysical, molecular, and functional characterization of circulating EVs in MF revealed a distinct signature marked by enlarged vesicle size, altered lipid and protein composition, and reduced ability to counteract a fibrosis-related phenotype. These findings support a potential role for circulating EVs in promoting marrow fibrosis and highlight their promise as a liquid biopsy approach for identifying biomarkers and potential therapeutic targets in MF.

Graphical Abstract