The role of telomeric protein dysfunction in human malignancy

National Institute On Aging

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Abstract

Previously, in collaboration with Division of Cancer Epidemiology and Genetics, National Cancer Institute, we have characterized the role of a POT1 variant in familial cutaneous malignant melanoma. Recently, they have conducted germline whole exome sequencing in patients and obligate carriers from families at high risk for human hematopoietic malignancies and identified the new POT1 variants in highly conserved regions of the gene. We found that these POT1 mutants do not bind to a single-stranded telomere oligonucleotide in vitro, suggesting that these mutations perturb POT1's ability to bind to the telomeric single-stranded termini. In addition, human cells expressing the POT1 mutants showed increased telomere length and telomere fragility. These findings strongly suggest that POT1 mutations play a role in hematopoietic tumorigenesis in these families. A manuscript reporting these results is in submission.