Deregulated Expression of Circular RNAs Is Associated with Immune Evasion and Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Fei Zhao; Xiaoyu Zhang; Xiaolei Pei; Donglin Yang; Mingzhe Han

doi:10.3390/genes13111986

Deregulated Expression of Circular RNAs Is Associated with Immune Evasion and Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Genes (Basel). 2022 Oct 31;13(11):1986. doi: 10.3390/genes13111986.

Authors

Fei Zhao¹, Xiaoyu Zhang¹, Xiaolei Pei¹, Donglin Yang¹, Mingzhe Han¹

Affiliation

¹ State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.

Abstract

Background: Circular RNAs (circRNAs) are a novel class of epigenetic regulators that participate in leukemogenesis. However, their roles in leukemia relapse after transplantation remain unclear.

Methods: We defined the circRNAs profile of the bone-marrow-enriched CD34⁺ cells from ten acute myeloid leukemia (AML) patients after transplantation (five relapse [RE] and five continuous complete remission [CR]) and four healthy controls (HCs) by RNA-seq. Differentially expressed circRNAs were validated using real-time quantitative polymerase chain reaction (RT-qPCR) in an independent cohort of six AML patients with pairwise samples at diagnosis and at relapse and six controls.

Results: The bioinformatics analysis revealed a distinct circRNAs profile in relapse patients compared with controls (CR or HCs), 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 the T cell receptor signaling pathway and lymphocyte differentiation. Moreover, we performed a protein-protein interaction network based on the immune-related genes and annotated 20 hub genes. The abnormal expression of hub genes was responsible for impairing T cell co-stimulation and activation, thus contributing to the immune escape of relapse blasts. We further constructed competing endogenous RNAs (ceRNA) regulatory networks based on immune-related genes and identified 10 key circRNAs that are associated with immune evasion. Six candidate circRNAs and their associated miRNA/mRNAs in the ceRNA network were randomly selected to be validated in another set by RT-qPCR.

Conclusions: CircRNAs dysregulation may be involved in the immune evasion of relapse blasts and is associated with AML relapse. Our results identify several promising biomarkers and might provide novel insights into the biology of AML relapse post-transplantation.

Keywords: acute myeloid leukemia; allogeneic hematopoietic stem cell transplantation; circRNA; immune evasion; relapse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Hematopoietic Stem Cell Transplantation*
Humans
Immune Evasion
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / therapy
MicroRNAs* / genetics
MicroRNAs* / metabolism
RNA, Circular / genetics
RNA, Messenger / genetics
Recurrence

Substances

RNA, Circular
RNA, Messenger
MicroRNAs

Grants and funding

This research was supported by grants from the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019XK320076), Fundamental Research Funds for the Central Universities (3332021055) and the National Natural Science Foundation of China (82100225).