Short telomeres limit braf V600E driven melanomagenesis in humanized telomere (HuT) mice

Telomere length influences genomic stability, immune function, and cancer susceptibility. Although mice are widely used to model tumorigenesis, their telomeres are much longer than humans and generally do not impose telomere-dependent proliferative limits. To determine how human-like telomeres affects melanoma development, we used humanized telomere (HuT) mice ( Tert h/h and Tert h/- ) with short, human-range telomeres (7-9 kb) and compared them to wildtype C57BL/6 ( Tert +/+ ) mice (~50 kb). Oncogenic Braf V600E was activated in Braf +/LSL-V600E ; Tyr::CreERT +/o transgenic mice at 2 months of age via tamoxifen, followed by weekly UV exposure to model chronic sunlight-driven melanoma. Tumor initiation, growth, and burden were monitored for 40-60 weeks. Histology, immunohistochemistry, qRT-PCR, Tissues and tumors were analyzed by H&E, IHC, qRT-PCR, gammaH2AX, TRF2, and telomere analysis assessed tumor biology and genomic integrity. Immune cell populations in peripheral blood, bone marrow, spleen, and tumors were analyzed by flow cytometry. Primary melanoma cell cultures were established and evaluated for Tert mRNA expression, telomerase activity, and somatic mutation analysis. Kaplan-Meier analysis showed significantly delayed melanoma onset in HuT mice compared to wild-type controls ( Tert h/h , p = 0.0053; Tert h/- , p = 0.0001; Log-rank test). Tert h/- mice developed fewer tumors per animal than both Tert h/h and wildtype mice. Interestingly, male Tert h/h mice, but not wildtype or Tert h/- mice, exhibited more rapid melanoma development than female littermates ( p = 0.0005), mirroring the higher melanoma incidence observed in men. Histological analysis confirmed nevi and pigmented cells. These findings demonstrate that short, humanized telomeres suppress Braf V600E -driven melanomagenesis in a genotype-, age-, and sex-dependent manner. The HuT mouse model provides a physiologically relevant platform to investigate telomere-regulated melanoma biology, immune-tumor interactions, and genomic instability, offering valuable insights for preclinical cancer research.