Telomere Maintenance-Associated Transcriptional States Mark a Proliferative and Genomically Unstable Axis in Myelodysplastic Syndromes

Abstract

Background: Myelodysplastic Syndromes (MDS) exhibit substantial biological heterogeneity driven by diverse molecular mechanisms. While telomere dysfunction has been implicated in MDS pathogenesis, its relationship to cellular programs, clonal architecture, and clinical outcomes remains incompletely defined.

Methods: We scored a curated telomere maintenance gene set by single sample Gene Set Enrichment (ssGSEA) score of 39 curated telomere maintenance genes in a public MDS transcriptomic cohort (n=183) and related it to pathway activity; we then examined mutation patterns, burden, and survival in an independent genomic cohort (n=3,323), using IPSS M risk to contextualize findings.

Results: Telomere maintenance activity was strongly positively associated with proliferative and cell cycle programs, including E2F targets (ρ≈0.84), G2M checkpoint (ρ≈0.83), and chromosomal instability (CIN70; ρ≈0.85), and negatively associated with p53 signaling and apoptosis (all FDR<0.05). Continuous analysis confirmed these relationships independent of categorical grouping. In the independent cohort, high-risk disease was characterized by increased mutation burden and enrichment of mutations in ASXL1 and spliceosome genes, while TP53 mutation remained the strongest predictor of inferior survival in multivariable analysis (HR=2.59). Survival analysis demonstrated significantly worse outcomes in high-risk patients (log-rank p<0.0001).

Interpretation: These findings identify a transcriptional state correlated with telomere maintenance gene expression that is associated with proliferative and genomically unstable features and adverse outcomes; causal effects on clonal progression cannot be inferred. Integration across cohorts supports an association between higher telomere maintenance gene expression, proliferative/ genomically unstable transcriptional programs, and adverse clinical context, but causal inferences cannot be made.

Conclusion: Telomere-associated transcriptional programs define a biologically and clinically relevant axis of disease in MDS, linking cellular state, genomic features, and patient outcomes.

Keywords: Myelodysplastic Syndromes; Telomere Maintenance; Chromosomal Instability; Clonal Hematopoiesis; ssGSEA; IPSS-M; TP53; ASXL1

Citation

Swarna Beesetti. Telomere Maintenance-Associated Transcriptional States Mark a Proliferative and Genomically Unstable Axis in Myelodysplastic Syndromes. WebLog J Genet Genomic Res. wjggr.2026. h2909. https://doi.org/10.5281/zenodo.22537185