Host microRNAs are differentially expressed in EBV+ Post-transplant Lymphoproliferative Disorder solid-organ transplant recipients

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. Previously, we demonstrated that EBV infection markedly reshapes the microRNA (miR) landscape in EBV+ B cell lines leading to increased IL-10 production. To establish the miRNAome of PTLD tumors we analyzed formalin-fixed, paraffin-embedded shavings of tumor tissues obtained from EBV+ PTLD SOT recipients by microarray analysis and quantitative PCR. The miRNAome of EBV+ PTLD tumors were distinctly different from EBV-PTLD tumors with reduced expression of miRs-17, 19 and 106a, and 194 among EBV+ PTLD tumors. miRs-17, 19, 106a, 155, and 194 were quantitated in the plasma and extracellular vesicles (EVs) from EBV+ PTLD+ SOT recipients and matched transplant controls. The plasma and EV levels of miRs-17, 19, 106a and 194 trended lower in the EBV+ PTLD+ group compared to matched controls, with miR-17 (plasma), miR-19 (EVs) and 106a (plasma and EVs) being significantly reduced. Importantly, the cell free miRs were contained primarily within the EVs. Further studies on the diagnostic, mechanistic, and therapeutic potential of these miRs in PTLD are warranted. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by NIH A1UO1AI104342 and UM2AI117870 (Rho). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by institutional review boards (IRBs) of Lucile Packard Children Hospital Stanford CA University of Texas Southwestern Medical Center Dallas TX University of Pittsburgh Medical Center Children Hospital Pittsburgh PA University of California Los Angeles CA University of Miami Health System Miami FL Medstar Georgetown Transplant Institute Washington DC Cincinnati Children Hospital Medical Center University of Cincinnati Cincinnati OH University Medical Center Schleswig-Holstein Campus Kiel Germany I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data for this study will be available from the corresponding author upon reasonable request. * miR : microRNA EBV : Epstein-Barr Virus PTLD : Post-Transplant Lymphoproliferative Disorder SOT : Solid Organ Transplant EV : Extracellular Vesicles qPCR : Quantitative Polymerase Chain Reaction CTOTC : Clinical Trials of Organ Transplantation in Children FFPE : Formalin-Fixed, Paraffin-Embedded DLBCL : Diffuse large B cell lymphoma