Abstract
BackgroundAcute myeloid leukemia can develop as myoblasts infiltrate into organs and tissues anywhere other than the bone marrow, which called extramedullary infiltration (EMI), indicating a poor prognosis. Circular RNAs (circRNAs) are a novel class of non-coding RNAs that feature covalently closed continuous loops, suggesting their potential as micro RNA (miRNA) “sponges” that can participate in biological processes and pathogenesis. However, investigations on circRNAs in EMI were conducted rarely. In this study, the overall alterations of circRNAs and their regulatory network between EMI and non-EMI AML were delineated.MethodsCircRNA and whole genome microarrays derived from EMI and non-EMI AML bone marrow mononuclear cells were carried out. Functional analysis was performed via Gene Ontology and KEGG test methods. The speculated functional roles of circRNAs were based on mRNAs and predicted miRNAs that played intermediate roles. Integrated bioinformatic analysis was conducted to further characterize the circRNA/miRNA/mRNA regulatory network and identify the functions of distinct circRNAs. The Cancer Genome Atlas (TCGA) data were acquired to evaluate the poor prognosis of distinct target genes of circRNAs. Reverse transcription-quantitative polymerase chain reaction was conducted to identify the expression of has_circRNA_0004520. Connectivity map (CMap) analysis was further performed to predict potential therapeutic agents for EMI.Results253 circRNAs and 663 genes were upregulated and 259 circRNAs and 838 genes were downregulated in EMI compared to non-EMI AML samples. GO pathways were enriched in progress including cell adhesion (GO:0030155; GO:0007155), migration (GO:0016477; GO:0030334), signal transduction (GO:0009966; GO:0007165) and cell–cell communication. Overlapping circRNAs envolved in pathways related to regulate cell–cell crosstalk, 17 circRNAs were chosen based on their putative roles. 7 target genes of 17 circRNAs (LRRK1, PLXNB2, OLFML2A, LYPD5, APOL3, ZNF511, and ASB2) indicated a poor prognosis, while overexpression of PAPLN and NRXN3 indicated a better one based on data from TCGA. LY-294002, trichostatin A and SB-202190 were identified as therapeutic candidates for EMI by the CMap analysis.ConclusionTaken together, this study reveals the overall alterations of circRNA and mRNA involved in EMI and suggests potential circRNAs may act as biomarkers and targets for early diagnosis and treatment of EMI.
Highlights
Acute myeloid leukemia can develop as myoblasts infiltrate into organs and tissues anywhere other than the bone marrow, which called extramedullary infiltration (EMI), indicating a poor prognosis
Acute myeloid leukemia (AML) is one of the most common hematologic malignancies that aggressive myeloid blasts derived from bone marrow (BM) have disseminated into the peripheral blood (PB), leading to the accumulation of myeloblasts in both the BM and PB [1]
CircRNA and differential gene expression in EMI and non‐EMI AML BM samples We examined 4 matched samples each of AML patients with or without EMI and healthy adults using circular RNA (circRNA) (Arraystar Human circRNA Array V2, 8 × 15 K, Arraystar, Rockville, MD, USA) and whole genome microarrays (Agilent, CA, USA) at the Department of Hematology of The First Affiliated Hospital of Harbin Medical University
Summary
Acute myeloid leukemia can develop as myoblasts infiltrate into organs and tissues anywhere other than the bone marrow, which called extramedullary infiltration (EMI), indicating a poor prognosis. The overall alterations of circRNAs and their regulatory network between EMI and non-EMI AML were delineated. EMI predicts a poor outcome of AML due to the destruction of important organs (e.g., in the CNS) and indicates that refractory and relapse leukemia are likely to develop [3]. Current studies on the molecular and cellular manifestations of EMI center on cytogenetic backgrounds [1, 5], gene mutations [6], cluster of differentiation (CD) markers and significant non-coding RNAs [7]. Clarifying the alterations of biological function underlying EMI may provide support to overcome the disease
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