title: Exogenous TERC alone can enhance proliferative potential, telomerase activity and telomere length in lymphocytes from dyskeratosis congenita patients.
abstract: Dyskeratosis congenita (DC) is an inherited multi-system disorder characterised by muco-cutaneous abnormalities, bone marrow failure and a predisposition to malignancy. Bone marrow failure is the principal cause of mortality and is thought to be the result of premature cell death in the haematopoietic compartment because DC cells age prematurely and tend to have short telomeres. DC is genetically heterogeneous and patients have mutations in genes that encode components of the telomerase complex (DKC1, TERC, TERT, NOP10 and NHP2), and telomere shelterin complex (TINF2), both important in telomere maintenance. Here, we transduced primary T lymphocytes and B lymphocyte lines established from patients with TERC and DKC1 mutations with wild type TERC-bearing lentiviral vectors. We found that transduction with exogenous TERC alone was capable of increasing telomerase activity in mutant T lymphocytes and B lymphocyte lines and improved the survival and thus overall growth of B-lymphocyte lines over a prolonged period, regardless of their disease mutation. Telomeres in TERC-treated lines were longer than in the untreated cultures. This is the first study of its kind in DC lymphocytes and the first to demonstrate that transduction with TERC alone can improve cell survival and telomere length without the need for exogenous TERT.
authors.affiliation: Centre for Paediatrics, Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. m.j.kirwan@qmul.ac.uk
authors.forename: Michael
authors.initials: M
authors.lastname: Kirwan
authors.forename: Richard
authors.initials: R
authors.lastname: Beswick
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Amit C
authors.initials: AC
authors.lastname: Nathwani
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Walne
authors.forename: Colin
authors.initials: C
authors.lastname: Casimir
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D019871:Dyskeratosis Congenita / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D012313:RNA / Q000008:administration & dosage* / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology / Q000473:pathology; D019098:Telomerase / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure; D014161:Transduction, Genetic / Q000379:methods; D055815:Young Adult
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase