Background: Cyclin D1 (encoded by CCND1) is a key cell cycle regulator frequently overexpressed in malignancies. Beyond its role in proliferation, emerging evidence suggests that CCND1 overexpression influences telomere maintenance and shelterin protein dynamics, particularly TRF2. However, tissue-specific effects during early development versus in established tumors remain poorly understood. Objective: To evaluate tissue morphology and determine whether increased CCND1 expression correlates with telomere shortening and altered TRF2 subcellular distribution in two distinct contexts: (1) prepubescent murine preB cells expressing v-abl/ccnd1, and (2) human non-small cell lung cancer (NSCLC) tissue. Methods: PreB cells from prepubescent *v-abl/ccnd1* transgenic mice were compared to wild-type controls. Human NSCLC resection specimens were stratified by CCND1 amplification status (FISH) and protein expression (IHC). Telomere length was measured by quantitative PCR and telomere restriction fragment analysis. TRF2 distribution was assessed by immunofluorescence and subcellular fractionation. Tissue evaluation included histopathological scoring and proliferative index (Ki-67). Results: In prepubescent *v-abl/ccnd1* mouse preB tissue, elevated CCND1 expression was associated with significant telomere shortening compared to controls (p<0.01) and a redistribution of TRF2 from telomeric foci to diffuse nucleoplasmic and perinuclear patterns. In human NSCLC, high CCND1 expression correlated with shortened telomeres (p<0.05) and similar TRF2 relocalization, predominantly in poorly differentiated tumors. Notably, TRF2 redistribution preceded overt telomere dysfunction-induced foci (TIFs) in both models. Conclusion: Increased CCND1 expression drives telomere shortening and alters TRF2 distribution in both prepubescent murine preB cells and human NSCLC, suggesting a conserved mechanism independent of developmental stage or species. Tissue evaluation reveals that CCND1-mediated TRF2 redistribution may be an early event in telomere destabilization, potentially contributing to genomic instability in lung cancer and lymphoid malignancies.
