title: A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition.
abstract: The TERT gene encodes for the reverse transcriptase activity of the telomerase complex and mutations in TERT can lead to dysfunctional telomerase activity resulting in diseases such as dyskeratosis congenita (DKC). Here, we describe a novel TERT mutation at position T1129P leading to DKC with progressive bone marrow (BM) failure in homozygous members of a consanguineous family. BM hematopoietic stem cells (HSCs) of an affected family member were 300-fold reduced associated with a significantly impaired colony forming capacity in vitro and impaired repopulation activity in mouse xenografts. Recent data in yeast suggested improved cellular checkpoint controls by mTOR inhibition preventing cells with short telomeres or DNA damage from dividing. To evaluate a potential therapeutic option for the patient, we treated her primary skin fibroblasts and BM HSCs with the mTOR inhibitor rapamycin. This led to prolonged survival and decreased levels of senescence in T1129P mutant fibroblasts. In contrast, the impaired HSC function could not be improved by mTOR inhibition, as colony forming capacity and multilineage engraftment potential in xenotransplanted mice remained severely impaired. Thus, rapamycin treatment did not rescue the compromised stem cell function of TERTT1129P mutant patient HSCs and outlines limitations of a potential DKC therapy based on rapamycin.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Stockklausner
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Raffel
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Klermund
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
authors.forename: Obul Reddy
authors.initials: OR
authors.lastname: Bandapalli
authors.affiliation: Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of the RWTH Aachen University, 52062 Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Beier
authors.affiliation: Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of the RWTH Aachen University, 52062 Aachen, Germany.
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
authors.affiliation: Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Bürger
authors.affiliation: Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Sven W
authors.initials: SW
authors.lastname: Sauer
authors.affiliation: Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Lorenz
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Tagliaferri
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nowak
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.|Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buergermeister
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Kerber
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genomics Core Facility, D 69117 Heidelberg, Germany.|European Molecular Biology Laboratory (EMBL), Genome Biology Unit and Molecular Medicine Partnership Unit, D 69117 Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Rausch
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit and Molecular Medicine Partnership Unit, D 69117 Heidelberg, Germany.
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany.|Institute of Molecular Biology gGmbH, gefördert durch die Böhringer Ingelheim Stiftung, 55128 Mainz, Germany.
authors.forename: Brian
authors.initials: B
authors.lastname: Luke
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D016922:Cellular Senescence; D019871:Dyskeratosis Congenita / Q000235:genetics*; D005260:Female; D006367:HeLa Cells; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D051379:Mice; D009154:Mutation; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D019098:Telomerase / Q000235:genetics*; D016615:Telomere
chemical_list: D018952:Antigens, CD34; D058570:TOR Serine-Threonine Kinases; C509186:TERT protein, human; D019098:Telomerase; D020123:Sirolimus
keywords: TERC; TERT; mTOR; rapamycin; senescence; sirolimus