From birth to disease: 3D telomere archtecture and aurora kinase changes in Down syndrome

Down syndrome (DS) is a chromosomal disorder associated with heightened genomic instability and a significantly increased risk of hematologic malignancies, particularly leukemia. In this study, we employed quantitative 3D telomere imaging and gene expression analysis to investigate nuclear telomeric architecture and aurora kinase (AURKA and AURKB) expression across three cytogenetically and clinically defined DS subgroups: pre-zygotic, post-zygotic, and DS-associated leukemia. Using TeloView® software, we assessed key telomere parameters, including number, length, aggregates, spatial organization, and nuclear volume. Our findings revealed distinct telomeric profiles among the subgroups, with the DS-leukemia group exhibiting significant telomere clustering, increased aggregate formation, and altered nuclear volume—hallmarks of advanced genomic instability. Notably, both AURKA and AURKB were markedly overexpressed in DS-leukemia samples, correlating with mitotic dysregulation and chromosomal aberrations. In contrast, DS-post-zygotic individuals displayed reduced telomeric alterations and low aurora kinase expression, suggesting a more stable genomic architecture. These results underscore the progressive nature of telomere dysfunction and aurora kinase upregulation in leukemogenesis among DS patients. The integration of 3D telomere profiling with mitotic gene expression offers novel biomarkers for disease stratification and may inform future diagnostic and therapeutic strategies in DS-associated leukemia.