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While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene  POT1 , which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated  POT1  display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional  POT1  allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous  POT1  p.Q199* as well as  POT1  knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between  POT1  p.Q199* and telomeric dysregulation and highlight  POT1  germline deficiency as a predisposition to myeloid malignancies in childhood.

Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood