title: POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia.
abstract: Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. We have analyzed exome sequencing data from 127 individuals with CLL and Sanger sequencing data from 214 additional affected individuals, identifying recurrent somatic mutations in POT1 (encoding protection of telomeres 1) in 3.5% of the cases, with the frequency reaching 9% when only individuals without IGHV@ mutations were considered. POT1 encodes a component of the shelterin complex and is the first member of this telomeric structure found to be mutated in human cancer. Somatic mutation of POT1 primarily occurs in gene regions encoding the two oligonucleotide-/oligosaccharide-binding (OB) folds and affects key residues required to bind telomeric DNA. POT1-mutated CLL cells have numerous telomeric and chromosomal abnormalities that suggest that POT1 mutations favor the acquisition of the malignant features of CLL cells. The identification of POT1 as a new frequently mutated gene in CLL may facilitate novel approaches for the clinical management of this disease.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ramsay
authors.forename: Víctor
authors.initials: V
authors.lastname: Quesada
authors.forename: Miguel
authors.initials: M
authors.lastname: Foronda
authors.forename: Laura
authors.initials: L
authors.lastname: Conde
authors.forename: Alejandra
authors.initials: A
authors.lastname: Martínez-Trillos
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.forename: David
authors.initials: D
authors.lastname: Rodríguez
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kwarciak
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garabaya
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gallardo
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.forename: María A
authors.initials: MA
authors.lastname: Blasco
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000595:Amino Acid Sequence; D002869:Chromosome Aberrations; D059472:Exome / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009841:Oligonucleotides / Q000378:metabolism; D009844:Oligosaccharides / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D000089804:Shelterin Complex; D016615:Telomere / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D009841:Oligonucleotides; D009844:Oligosaccharides; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins