Variant rs715020 is associated with childhood acute lymphoblastic leukemia risk through reducing QKI expression and promoting cell growth

In recent years, the newly discovered alternative back-splicing (ABS), as one of the modes of alternative splicing, can generate a large number of circular RNA (circRNA) molecules. Owing to their unique structures and physiological characteristics, these circRNA have been proven to play a significant role in acute lymphoblastic leukemia (ALL). However, the regulatory mechanism of ABS remains unclear. Evidence regarding single-nucleotide polymorphisms (SNP) of ABS protein and circRNA biogenesis key regulator genes and the risk of ALL is still fairly elusive. To evaluate these genes SNPs susceptible to ALL, we carried out a case–control study genotyping 6 SNPs in 782 cases of ALL and 1077 controls. Stratified analysis and prognosis analysis were conducted, and then we investigated the impact of SNP on QKI expression and elucidated the cytological functions of QKI . Finally functional analysis in silico was also performed. We found two genetic variants, QKI (rs715020 G > A) and ILF3 (rs3810156 C > G), exhibited a significant association with increased susceptibility to ALL. These two SNP loci exhibit significant associations with the susceptibility to distinct clinical subtypes of ALL. Of note, the polymorphisms QKI rs715020 was identified as a predictor of chemotherapy outcome. Mechanistically, rs715020 G > A indeed affected the expression level of QKI , which showed lower mRNA and might be via altering the binding to JUN. Low expression of QKI accelerates cell cycle phase transition and promotes malignant proliferation in leukemia cells. Our findings demonstrate that the QKI rs715020 variant is associated with the risk of ALL, exhibits potential as a biomarker for chemotherapy regimen selection, and plays functional roles in leukemia cells, thereby underscoring its clinical relevance in ALL treatment.