Abstract 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 (Terth/h and Terth/-) with short, human-range telomeres (7-9 kb) and compared them to wildtype C57BL/6 (Tert+/+) mice (∼50 kb). Oncogenic BrafV600E 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 Terth/-, p = 0.0001; Log-rank test). Terth/- mice developed fewer tumors per animal than both Terth/h and wildtype mice. Interestingly, male Terth/h mice, but not wildtype or Terth/- 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 BrafV600E-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. Citation Format: Md Hazzaz Bin Kabir, Jiawei Liu, Fan Zhang, Kenneth I Porter, Gavin P. Robertson, Jiyue Zhu. Short telomeres limit brafV600E driven melanomagenesis in humanized telomere (HuT) mice abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3378.
Kabir et al. (Fri,) studied this question.