MicroRNA composition of plasma extracellular vesicles: a harbinger of late cardiotoxicity in long-term survivors of acute lymphoblastic leukemia treated with doxorubicin

The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies. Here we have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 childhood acute lymphoblastic leukemia survivors treated with doxorubicin and 61 healthy controls (254 samples in total). We analyzed processes regulated by differentially expressed miRNA and cross-validated our results with the data of patients with clinically manifested cardiomyopathies. Our analyses indicate that the circulating compartment used for inspection should be selected with particular attention. miRNAs contained within EVs may be particularly informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin, transforming growth factor beta or epidermal growth factor receptors (ErbB). Among miRNAs differentially expressed in vesicles, which additionally are also most variable between groups, we identified those correlated with echocardiographic parameters, including miR-144-3p and miR-423-3p and respectively for plasma miRNAs: let-7g-5p, miR-16-2-3p. Among these, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is also differentially expressed in the circulation of patients with dilated cardiomyopathy. We also show that in ALL survivors' distribution of particular miRNAs, e.g., miR-184 between plasma and EVs is different than in healthy controls. This suggests persistent alterations within the cellular sorting and exporting system.