Dataset Information

Epigenetic Impairment of tumor potential of AML-derived extracellular vesicles

ABSTRACT: The biological active cargo of leukemia-derived extracellular vesicles (EVs) favours a wide variety of cancer-supportive mechanisms, including aberrant proliferative signalling, immune escape and drug resistance. However, whether and in which extent anti-neoplastic drugs affect EV cargo sorting is often underestimated. Vorinostat, also known as SAHA, has shown promising results against leukemia , and reached important clinical goals when combined with other therapeutics. Nevertheless, SAHA-mediated effects on intercellular communication via EVs remains unknown. Here, we found SAHA to significantly affects the overall cargo associated with leukemia-derived EVs. Interestingly, SAHA differently affects the intracellular and vesicular levels of miR194-5p and BCLAF1 ratio, which imbalance was previously shown to regulate cell survival and differentiation in leukemic cells. Moreover, in silico evaluations predicted SAHA to skew the tumoral potential ascribed to leukemic EVs, hypothesis confirmed by functional evaluations. Finally, EVs from SAHA-treated leukemic cells may condition the sensitivity of surrounding cancer cells to other antineoplastic agents. Altogether we showed that SAHA leads leukemic cells towards apoptosis while reverting the oncologic significance ascribed to leukemia-derived EVs, eventually affecting the efficacy, and therefore selection, of other therapeutics to use for combinatorial purposes.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Myeloid Leukemia

SUBMITTER: Maria Concetta Cufaro

LAB HEAD: Damiana Pieragostino

PROVIDER: PXD042168 | Pride | 2025-05-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20211118_CTRL_U937_EVs_02.raw	Raw
	20211118_CTRL_U937_EVs_03.raw	Raw
	20211118_CTRL_U937_EVs_04.raw	Raw
	20211118_SAHA_U937_EVs_02.raw	Raw
	20211118_SAHA_U937_EVs_03.raw	Raw

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Publications

Vorinostat impairs the cancer-driving potential of leukemia-secreted extracellular vesicles.

Massaro Crescenzo C Sgueglia Giulia G Muro Annamaria A Pieragostino Damiana D Lanuti Paola P Cufaro Maria Concetta MC Giorgio Cristina C D'Agostino Erika E Torre Laura Della LD Baglio Serena Rubina SR Pirozzi Marinella M De Simone Mariacarla M Altucci Lucia L Dell'Aversana Carmela C

Journal of translational medicine 20250410 1

<h4>Background</h4>Leukemia-secreted extracellular vesicles (EVs) carry biologically active cargo that promotes cancer-supportive mechanisms, including aberrant proliferative signaling, immune escape, and drug resistance. However, how antineoplastic drugs affect EV secretion and cargo sorting remains underexplored.<h4>Methods</h4>Leukemia-secreted extracellular vesicles (EVs) were isolated by Differential UltraCentrifugation, and their miRNome and proteomic profiling cargo were analyzed followin ...[more]

PMID: 40211278

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.