The role of IKZF1 rs4132601 and Δ4-7 somatic deletion in acute lymphoblastic leukemia: a bioinformatics and case-control study.

Objectives: IKZF1 is a key regulator of lymphocyte differentiation, and its alterations are associated with increased risk and poor outcomes in acute lymphoblastic leukemia (ALL). This study examines the association of IKZF1 rs4132601 polymorphism and Δ4-7 somatic deletion with the susceptibility to ALL while also analyzing their molecular implications through bioinformatics.

Methods: This case-control study was conducted on 58 pediatric patients diagnosed with ALL and 150 healthy controls. Genotyping for the IKZF1 rs4132601 variant was performed by PCR followed by sequencing, while the Δ4-7 deletions were identified using multiplex PCR. Bioinformatics analyses were used to calculate the difference in free energy of hybridization for each wild-type vs. the variant allele and analyze potential disruptions in putative miRNA-binding sites of IKZF1 3'UTR and changes in RNA secondary structure.

Results: The presence of the rs4132601 G allele was significantly associated with a reduced risk of ALL development [OR(95%ci), 0.36(0.19,0.69)], and a strong association with the Δ4-7 deletion was noted [RR(95%ci), 8.33(1.57-10.69)]. The rs4132601 polymorphism disrupts miRNA binding sites, particularly miR-1261, miR-524-3p, and miR-525-3p, potentially impairing post-transcriptional control of IKZF1. Bioinformatics analyses further indicate that the G allele stabilizes the RNA secondary structure, which hinders normal IKZF1 post-transcriptional regulation and promotes leukemogenesis.

Discussion: Our study underscores the association between the rs4132601 polymorphism and Δ4-7 deletion and heightened risk of pediatric ALL. We favor the notion that the rs4132601G allele contributes to leukemogenesis by affecting miRNA-mediated regulation and RNA structural stability. These findings support the potential of IKZF1-targeted, miRNA-based therapies in pediatric ALL.