Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood.

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 , which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated 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 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous p.Q199* as well as knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between p.Q199* and telomeric dysregulation and highlight germline deficiency as a predisposition to myeloid malignancies in childhood.