MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools

SIMPLE SUMMARY: MicroRNAs (miRNAs) have been under the spotlight for the last three decades. These non-coding RNAs seem to be dynamic regulators of mRNA stability and translation, in addition to interfering with transcription. Circulating miRNAs play a critical role in cell-to-cell interplay; therefore, they can serve as disease biomarkers. Meta-analysis of published data revealed that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against acute lymphoblastic leukemia (ALL) in children. Reanalysis of small RNA-seq data with novel tools identified significantly overexpressed members of the miR-128, miR-181, miR-130 and miR-17 families and significantly lower expression of miR-30, miR-24-2 and miR143~145 clusters, miR-574 and miR-618 in pediatric T-ALL cases compared with controls. Inconsistencies in methodology and study designs in most published material preclude reproducibility, and further cohort studies need to be conducted in order to empower novel tools, such as ALLSorts and RNAseqCNV. ABSTRACT: MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against ALL occurrence in children; (ii) no significant association between rs2910164 genotypes in miR-146a and childhood ALL; and (iii) SNPs in DROSHA, miR-449b, miR-938, miR-3117 and miR-3689d-2 genes seem to be associated with susceptibility to B-ALL in childhood. A review of published literature on differential expression of miRNAs in children with ALL compared with controls revealed a significant upregulation of the miR-128 family, miR-130b, miR-155, miR-181 family, miR-210, miR-222, miR-363 and miR-708, along with significant downregulation of miR-143 and miR-148a, seem to have a definite role in childhood ALL development. MicroRNA signatures among childhood ALL subtypes, along with differential miRNA expression patterns between B-ALL and T-ALL cases, were scrutinized. With respect to T-ALL pediatric cases, we reanalyzed RNA-seq datasets with a robust and sensitive pipeline and confirmed the significant differential expression of hsa-miR-16-5p, hsa-miR-19b-3p, hsa-miR-92a-2-5p, hsa-miR-128-3p (ranked first), hsa-miR-130b-3p and -5p, hsa-miR-181a-5p, -2-3p and -3p, hsa-miR-181b-5p and -3p, hsa-miR-145-5p and hsa-miR-574-3p, as described in the literature, along with novel identified miRNAs.