circRNAs profile in the bone marrow-enriched CD34+ cells from 10 AML patients after transplantation (5 in relapse [RE] and 5 in continuous complete remission [CR]) and 4 healthy controls (HCs) by whole transcriptome sequencing. Deregulated expression of Circular RNAs drives immune evasion and leukemia relapse after allogeneic hematopoietic stem cell transplantation

Background Relapse is currently the dominant cause of high mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML). Recent studies have elucidated that immune signature drives leukemia relapse. Circular RNAs (circRNAs) deregulation has been extensively studied in regulating immune responses and leukemogenesis. However, their roles in the AML relapse after allo-HSCT remain unclear. Methods We defined the circRNAs profile in the bone marrow-enriched CD34+ cells from 10 AML patients after transplantation (5 in relapse [RE] and 5 in continuous complete remission [CR]) and 4 healthy controls (HCs) by whole transcriptome sequencing. The differential expression of circRNAs were validated using real-time quantitative polymerase chain reaction (RT-qPCR) with an independent cohort of 27 participants. Results Bioinformatics analysis revealed a unique expression profile of circRNAs in relapsed patients compared with controls (CR or HC), while there was no significant difference between CR and HCs. Functional enrichment analysis demonstrated that mRNAs co-expressed with identified circRNAs were primarily involved in immune-related pathways, including T cell receptor signaling pathway and lymphocyte differentiation. Moreover, we performed protein-protein interaction network based on the immune-related genes between relapses vs controls and annotated 20 hub genes. Abnormal expression of hub genes is responsible for impairing T cell co-stimulation and activation, thus contributing to immune escape of relapse blasts. We further constructed competing endogenous RNAs (ceRNA) regulatory network based on immune-related genes and identified 10 key circRNAs contributed to immune evasion. Six candidate circRNAs were randomly selected to validate in another set by RT-qPCR. Conclusion CircRNAs deregulation is implicated in immune escape of relapse blasts and contributes to leukemic relapse. Our results provide novel insights on the biology of relapse blasts and potential innovative strategy to cure AML relapse after allo-HSCT.