Association of FOXO3a (rs4946936) genetic variant with chronic myeloid leukemia susceptibility and imatinib response in a cohort of Egyptian patients

Purpose Chronic myeloid leukemia (CML) is characterized by the presence of breakpoint cluster region - Abelson murine leukemia viral oncogene homolog 1 fusion gene (BCR-ABL1) fusion gene, constitutively activating signaling pathways, including PI3K/AKT, causing uncontrolled myeloid proliferation. Forkhead box O3a (FOXO3a), a transcription factor involved in apoptosis and cell cycle arrest, is inhibited through BCR-ABL1–mediated activation of the PI3K/AKT pathway, supporting leukemogenesis. Despite the strong effect of tyrosine kinase inhibitors (TKIs) including imatinib (IM) on managing CML, still around 25–30% of patients fail to achieve optimal responses. Host genetic variations, including single nucleotide variants (SNV) in FOXO3a, may therefore influence both disease susceptibility and treatment response. This study investigated the association of FOXO3a (rs4946936) SNV with CML susceptibility and IM response in an Egyptian cohort. Patients and methods FOXO3a (rs4946936) genotyping of 56 CML patients and 50 healthy controls was done by PCR-RFLP. Response to IM was assessed according to European Leukemia Net (ELN) 2020 guidelines. Results Genotype and allele frequencies did not differ significantly between patients and controls ( P =0.338, P =0.512). No association was found with molecular response ( P =0.331). However, the variant (TT) genotype was significantly associated with poorer hematological response, reflected by higher myelocyte, metamyelocyte, and basophil counts at follow-up ( P =0.005, P =0.017, P =0.017, respectively). Conclusion FOXO3a (rs4946936) SNV does not influence susceptibility to CML or molecular response to IM. Nevertheless, the TT genotype may be linked to impaired hematological response, suggesting a potential modulatory role, requiring validation in larger, multicenter studies.