Background: Evidence for an inherited genetic risk for pediatric acute lymphoblastic leukemia has been provided in several studies. Most of them focused on coding regions. However, those regions represent only 1.5% of the entire genome. In acute lymphoblastic leukemia (ALL), it has been suggested that the expression of microRNAs (miRNAs) is dysregulated, which suggests that they may have a role in ALL risk. Changes in miRNA function may occur through single-nucleotide polymorphisms (SNPs). Therefore, the aim of this study was to evaluate whether polymorphisms in premiRNAs, and/or miRNA-processing genes, contribute to a predisposition for childhood ALL. Methods: In this study, we analyzed 118 SNPs in pre-miRNAs and miRNA-processing genes in 213 B-cell ALL patients and 387 controls. results: We found 11 SNPs significantly associated with ALL susceptibility. These included three SNPs present in miRNA genes (miR-612, miR-499, and miR-449b) and eight SNPs present in six miRNA biogenesis pathway genes (TNRC6B, DROSHA, DGCR8, EIF2C1, CNOT1, and CNOT6). Among the 118 SNPs analyzed, rs12803915 in mir-612 and rs3746444 in mir-499 exhibited a more significant association, with a P value <0.01. conclusion: The results of this study indicate that SNP rs12803915 located in pre-mir-612, and SNP rs3746444 located in pre-mir-499, may represent novel markers of B-cell ALL susceptibility. a cute lymphoblastic leukemia (ALL) is the most common pediatric hematological malignancy in developed countries. Its etiology is believed to be multifactorial, with both environmental and genetic risk factors being relevant (1). Recently, several studies have provided evidence for an inherited genetic risk for pediatric ALL (2,3). Most of these studies focused on the coding regions of these genetic components. However, this represents only ~1.5% of the entire genome, and noncoding regions of the genome have also been shown to mediate regulatory functions. For example, microRNAs (miRNAs) are a class of small noncoding RNA molecules that regulate gene expression at the posttranscriptional level by binding to the 3′ untranslated region of a target gene (4). This can lead to an inhibition of translation or enhanced degradation of a target mRNA (Figure 1). Primary double-stranded miRNA transcripts (pri-miRNA) are processed in the nucleus by microprocessor machinery, which includes DROSHA RNase and the double-stranded RNA-binding protein, DGCR8. A hairpin precursor miRNA molecule of 70-100 nucleotides (pre-miRNA) is then produced, and its translocation into the cytoplasm is facilitated by RAN GTPase and Exportin 5 (XPO5). In the cytoplasm, pre-miRNAs are further processed by a protein complex that includes DICER1, TRBP, EIF2C1, EIF2C2, GEMIN3, and GEMIN4, resulting in the production of mature miRNAs (4). It has been predicted that there are more than 1,000 miRNA genes in the human genome (5), and ~30% of human genes are regulated by miRNAs.In the past few years, it was suggested that miRNAs in ALL are dysregulated. For example, in the study of Zhang ...

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The intron 3 of ARID5B gene was found to be strongly associated with B-ALL risk in the Spanish population examined. However, neither CNVs nor changes in mRNA expression were found to be responsible for this association.

The locus CDKN2A/B (9p21.3), which comprises the tumor suppressors genes CDKN2A and CDKN2B and the long noncoding RNA (lncRNA) known as ANRIL (or CDKN2B-AS), was associated with childhood acute lymphoblastic leukemia (ALL) susceptibility in several genome wide association studies (GWAS). However, the variants associated in the diverse studies were different. Recently, new and independent SNPs deregulating the locus function were also identified in association with ALL risk. This diversity in the results may be explained because different variants in each population could alter CDKN2A/B locus function through diverse mechanisms. Therefore, the aim of this study was to determine whether the annotated risk variants in the CDKN2A/B locus affect the susceptibility of B cell precursor ALL (B-ALL) in our Spanish population and explore if other SNPs altering additional regulatory mechanisms could be also involved. We analyzed the four SNPs proposed by GWAs and two additional SNPs in miRNA binding sites in 217 pediatric patients with B-ALL and 330 healthy controls. The SNPs rs2811712, rs3731249, rs3217992 and rs2811709 were associated with B-ALL susceptibility in our Spanish population. ALL subtypes analyses showed that rs2811712 was associated with B-hyperdiploid ALL. These results provide evidence for the influence of genetic variants at CDKN2A/B locus with the risk of developing B-ALL.

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