biostudies-literatureKim WTAmerican Cancer SocietyAlexander and Margaret Stewart TrustNIDDK NIH HHSPew Charitable TrustsNCI NIH HHSe107346https://www.ebi.ac.uk/biostudies/studies/S-EPMC8204863biostudies-literatureUnknown40(12)Mutations in the shelterin protein POT1 are associated with chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, angiosarcoma, melanoma, and other cancers. These cancer-associated POT1 (caPOT1) mutations are generally heterozygous, missense, or nonsense mutations occurring throughout the POT1 reading frame. Cancers with caPOT1 mutations have elongated telomeres and show increased genomic instability, but which of the two phenotypes promotes tumorigenesis is unclear. We tested the effects of CAS9-engineered caPOT1 mutations in human embryonic and hematopoietic stem cells (hESCs and HSCs, respectively). HSCs with caPOT1 mutations did not show overt telomere damage. In vitro and in vivo competition experiments showed the caPOT1 mutations did not confer a selective disadvantage. Since DNA damThe EMBO journalCancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.PMC8204863R01 CA196884U54 DK106829133396‐RSG‐19‐029‐01‐DMCDrubin CHennick KJohnson JForster RChoo SKim WTFinnerty BShort SBMcMaster MLHockemeyer DfalseCancer-associated POT1 mutations lead to telomere elongation without induction of a DNA damage response.Mutations in the shelterin protein POT1 are associated with chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, angiosarcoma, melanoma, and other cancers. These cancer-associated POT1 (caPOT1) mutations are generally heterozygous, missense, or nonsense mutations occurring throughout the POT1 reading frame. Cancers with caPOT1 mutations have elongated telomeres and show increased genomic instability, but which of the two phenotypes promotes tumorigenesis is unclear. We tested the effects of CAS9-engineered caPOT1 mutations in human embryonic and hematopoietic stem cells (hESCs and HSCs, respectively). HSCs with caPOT1 mutations did not show overt telomere damage. In vitro and in vivo competition experiments showed the caPOT1 mutations did not confer a selective disadvantage. Since DNA dam2021-01-01T00:00:00Z2021 Jun2025-04-04T03:30:49.46Z2022-02-10T16:52:36.151ZS-EPMC82048633393439410.15252/embj.2020107346