Background Circular RNAs (circRNAs) constitute a family of transcripts with unique structures and have been confirmed to be critical in tumorigenesis and to be potential biomarkers or therapeutic targets. However, only a few circRNAs have been functionally characterized in pediatric acute myeloid leukemia (AML). Methods Here, we investigated the expression pattern of circRNAs in pediatric AML using a circRNA microarray. The characteristics, potential diagnostic value, and prognostic significance of circRNF220 were evaluated. A series of functional experiments were performed to investigate the role of circRNF220 in primary pediatric AML cells. Then we investigated the aberrant transcriptional networks regulated by circRNF220 in primary AML cells by RNA-seq. Furthermore, biotin RNA pulldown assays were implemented to verify the relationship between circRNF220 and miR-30a. Results We identified a circRNA, circRNF220, which was specifically abundant in and accumulated in the peripheral blood and bone marrow of pediatric patients with AML. It could distinguish AML from ALL and other hematological malignancies with high sensitivity and specificity. Significantly, circRNF220 expression independently predicted prognosis, while high expression of circRNF220 was an unfavorable prognostic marker for relapse. Furthermore, we characterized the function of circRNF220 and found that circRNF220 knockdown specifically inhibited proliferation and promoted apoptosis in AML cell lines and primary cells. Mechanistically, circRNF220 may act as an endogenous sponge of miR-30a to sequester miR-30a and inhibit its activity, which increases the expression of its targets MYSM1 and IER2 and implicated in AML relapse. Conclusions Collectively, these findings demonstrated that circRNF220 could be highly efficient and specific for the accurate diagnosis of pediatric AML, with implications for relapse prediction.

Neuroblastoma is a pediatric malignancy, and the clinical phenotypes range from localized tumors with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40%, despite intensive therapy. Emerging evidence suggests that aberrant miRNA regulation plays a role in neuroblastoma, but the miRNA functions and mechanisms remain unknown. miR-181 family members were detected in 32 neuroblastoma patients, and the effects of miR-181a/b on cell viability, invasion, and migration were evaluated in vitro and in vivo. A parallel global mRNA expression profile was obtained for neuroblastoma cells overexpressing miR-181a. The potential targets of miR-181a/b were validated. miR-181a/b expression levels were positively associated with MYCN amplification and neuroblastoma aggressiveness. Moreover, ectopic miR-181a/b expression significantly induced the growth and invasion of neuroblastoma cells in vitro and in vivo. Microarray analysis revealed that mRNAs were consistently downregulated after miR-181a overexpression, leading to cell migration. In addition, the expression of ABI1 was suppressed by miR-181a/b, and ABI1 was validated as a direct target of miR-181a/b. We concluded that miR-181a/b were significantly upregulated in aggressive neuroblastoma, which enhanced its tumorigenesis and progression by suppressing the expression of ABI1.

ObjectiveTo reveal the contributing role of METTL3 gene SNPs in pediatric ALL risk.Patients and MethodsA total of 808 pediatric ALL cases and 1,340 cancer-free controls from five hospitals in South China were recruited. A case-control study by genotyping three SNPs in the METTL3 gene was conducted. Genomic DNA was abstracted from peripheral blood. Three SNPs (rs1263801 C>G, rs1139130 A>G, and rs1061027 A>C) in the METTL3 gene were chosen to be detected by taqman real-time polymerase chain reaction assay.ResultsThat rs1263801 C>G, rs1139130 A>G, and rs1061027 A>C polymorphisms were significantly associated with increased pediatric ALL risk was identified. In stratification analyses, it was discovered that rs1263801 CC, rs1061027 AA, and rs1139130 GG carriers were more likely to develop ALL in subgroups of common B-ALL, MLL gene fusion. Rs1263801 CC and rs10610257 AA carriers were more possible to increase the risk of ALL in subgroups of low hyperdiploid, and all of these three SNPs exhibited a trend toward the risk of ALL. All of these three polymorphisms were associated with the primitive/naïve lymphocytes and MRD in marrow after chemotherapy in ALL children. Rs1263801 CC and rs1139130 AA alleles provided a protective effect on MRD ≥0.01% among CCCG-treated children. As for rs1139130, AA alleles provided a protective effect on MRD in marrow ≥0.01% on 33 days and 12 weeks among CCCG-treated children, but provided a risk effect on MRD in the marrow ≥0.01% among SCCLG-treated children. As for rs1263801 CC and rs1139130 AA, these two alleles provided a protective effect on MRD in the marrow ≥0.01% among CCCG-treated children.ConclusionIn this study, we revealed that METTL3 gene polymorphisms were associated with increased pediatric ALL risk and indicated that METTL3 gene polymorphisms might be a potential biomarker for choosing ALL chemotherapeutics.

Background/Aim Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. METTL14 , an N 6 -methyladenosine (m 6 A) modification protein, plays several roles in cancer development and is involved in the pathogenesis of various types of cancers. However, the role of METTL14 gene single nucleotide polymorphisms (SNPs) in pediatric ALL susceptibility remains to be investigated. Methods A case-control design and multinomial logistic regression were used to develop models to estimate the overall risk for pediatric ALL and three METTL14 gene SNPs (rs298982 G/A, rs298981 A/G and rs1064034 T/A) in 808 cases and 1340 controls, which were genotyped using a TaqMan assay. The associations were estimated by odds ratios (ORs) with their 95% confidence intervals (CIs). Furthermore, stratified analysis was performed to explore associations of rs298982 and rs1064034 with pediatric ALL susceptibility in terms of age, sex, immunophenotype, minimal residual disease (MRD), and other clinical characteristics. Results Among the three analyzed SNPs, rs298982 G/A and rs1064034 T/A exhibited a significant association with decreased childhood ALL risk, while rs298981 A/G exhibited no difference. In stratified analysis, rs298982 GA/AA and rs1064034 TA/AA had a protective effect in children <120 months of age and males, common B ALL, TEL-AML, non gene fusion, normal diploid, and high WBC. However, the rs1064034 TA/AA genotype was associated with an increased risk of mixed immunophenotyping. Compared with the reference haplotype GAT, haplotypes CAA, CGT and CGA were significantly associated with elevated ALL risk, while haplotype GGT was significantly associated decreased ALL risk. Moreover, subjects carrying rs298982 A or rs1064034 A exhibited less minimal MRD after induced chemotherapy. Functional annotations revealed that METTL14 gene SNPs rs298982 G/A and rs1064034 T/A could be potential functional variants. Conclusion In conclusion, METTL14 gene polymorphisms influence the risk of ALL in southern Chinese children and might be potential biomarkers for pediatric ALL susceptibility and chemotherapeutics.

Acute lymphoblastic leukemia (ALL) is the most frequently diagnosed cancer in children and single‐nucleotide polymorphisms (SNPs) in certain genes influence risk of ALL. Although FOXO3 had been demonstrated to be involved leukemia, the role of FOXO3 polymorphisms was still not clear. In the present study, we explored the association of FOXO3 SNPs with ALL risk in Chinese children. We genotyped four polymorphisms (rs17069665 A>G, rs4945816 T>C, rs4946936 C>T, and rs9400241 A>C) of FOXO3 in 425 ALL cases and 1339 health controls. The associations were estimated by odds ratios (ORs) with their 95% confidence intervals (CIs). Further analyses were performed to explore associations of rs17069665 and rs9400241 with ALL susceptibility in terms of age, gender, immunophenotype, minimal residual disease (MRD), and other clinical characteristics. We found rs17069665 related to the increased ALL risk (OR = 1.76; 95% CI = 1.02‐3.04), rs9400241 related to decreased ALL risk (OR = 0.80; 95% CI = 0.64‐0.99). The effects of rs17069665 on ALL risk were more predominant in males and children < 10 years, and patients with lower rates of platelet or neutrophil. As for rs9400241, the effects were more predominant in children < 10 years, and in patients with pre B ALL, positive MRD, anemia, or hepatomegaly. In conclusion, FOXO3 gene polymorphisms influence the risk of ALL in children and might be a potential biomarker for ALL susceptibility.