title: Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of dyskeratosis congenita.
abstract: TRF1 is part of the shelterin complex, which binds telomeres and it is essential for their protection. Ablation of TRF1 induces sister telomere fusions and aberrant numbers of telomeric signals associated with telomere fragility. Dyskeratosis congenita is characterized by a mucocutaneous triad, bone marrow failure (BMF), and presence of short telomeres because of mutations in telomerase. A subset of patients, however, show mutations in the shelterin component TIN2, a TRF1-interacting protein, presenting a more severe phenotype and presence of very short telomeres despite normal telomerase activity. Allelic variations in TRF1 have been found associated with BMF. To address a possible role for TRF1 dysfunction in BMF, here we generated a mouse model with conditional TRF1 deletion in the hematopoietic system. Chronic TRF1 deletion results in increased DNA damage and cellular senescence, but not increased apoptosis, in BM progenitor cells, leading to severe aplasia. Importantly, increased compensatory proliferation of BM stem cells is associated with rapid telomere shortening and further increase in senescent cells in vivo, providing a mechanism for the very short telomeres of human patients with mutations in the shelterin TIN2. Together, these results represent proof of principle that mutations in TRF1 lead to the main clinical features of BMF.
authors.affiliation: Telomere and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Fabian
authors.initials: F
authors.lastname: Beier
authors.forename: Miguel
authors.initials: M
authors.lastname: Foronda
authors.forename: Paula
authors.initials: P
authors.lastname: Martinez
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology*; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D016922:Cellular Senescence; D003114:Colony-Forming Units Assay; D004249:DNA Damage; D004195:Disease Models, Animal; D019871:Dyskeratosis Congenita / Q000209:etiology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006413:Hematopoietic System / Q000473:pathology*; D006457:Hemoglobinuria, Paroxysmal / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010198:Pancytopenia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000473:pathology; D015996:Survival Rate; D016615:Telomere / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics; D035321:Telomeric Repeat Binding Protein 1 / Q000502:physiology*
chemical_list: C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; C045073:Cre recombinase; D019426:Integrases