Soltani Ismail, Bahia Wael, Slaymi Chaker, Gharbi Hanene, Hasni Yosra, Ferchichi Salima, Menif Samia, Almawi Wassim Y
Laboratory of Clinical and Molecular Biology, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, LR24ES15, Tunisia.
Faculty of Sciences of Gafsa, Department of Biology, University of Gafsa, Campus Sidi Ahmed Zarouk, Gafsa, 2112, Tunisia.
Mol Biol Rep. 2025 May 22;52(1):487. doi: 10.1007/s11033-025-10608-x.
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.
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.
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.
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.
IKZF1是淋巴细胞分化的关键调节因子，其改变与急性淋巴细胞白血病（ALL）的风险增加和不良预后相关。本研究探讨IKZF1 rs4132601多态性和Δ4-7体细胞缺失与ALL易感性的关联，并通过生物信息学分析它们的分子影响。
本病例对照研究对58例诊断为ALL的儿科患者和150例健康对照进行。通过PCR随后测序对IKZF1 rs4132601变体进行基因分型，同时使用多重PCR鉴定Δ4-7缺失。生物信息学分析用于计算每个野生型与变体等位基因杂交自由能的差异，并分析IKZF1 3'UTR假定miRNA结合位点的潜在破坏以及RNA二级结构的变化。
rs4132601 G等位基因的存在与ALL发生风险降低显著相关[比值比（95%置信区间），0.3（0.19，0.69）]，并且与Δ4-7缺失有强关联[相对风险（95%置信区间），8.33（1.57 - 10.69）]。rs4132601多态性破坏miRNA结合位点，特别是miR-1261、miR-524-3p和miR-525-3p，可能损害IKZF1的转录后调控。生物信息学分析进一步表明，G等位基因稳定RNA二级结构，这阻碍了正常的IKZF1转录后调控并促进白血病发生。
我们的研究强调了rs4132601多态性和Δ4-7缺失与儿科ALL风险增加之间的关联。我们支持rs4132601G等位基因通过影响miRNA介导的调控和RNA结构稳定性促进白血病发生的观点。这些发现支持了针对IKZF1的基于miRNA的疗法在儿科ALL中的潜力。
