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Research Paper|Volume 7, Issue 11|pp 911—927

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

Clemens Stockklausner1, Simon Raffel2,3,4, Julia Klermund5, Obul Reddy Bandapalli1, Fabian Beier6, Tim H. Brümmendorf6, Friederike Bürger7, Sven W. Sauer7, Georg F. Hoffmann7, Holger Lorenz5, Laura Tagliaferri1, Daniel Nowak8, Wolf-Karsten Hofmann8, Rebecca Buergermeister1,5, Carolin Kerber1, Tobias Rausch9,10, Jan O. Korbel10, Brian Luke5,11, Andreas Trumpp2,3,4, Andreas E. Kulozik1
  • 1Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
  • 2Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • 3Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
  • 4German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
  • 5Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany
  • 6Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty of the RWTH Aachen University, 52062 Aachen, Germany
  • 7Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany
  • 8Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, 68167 Mannheim, Germany
  • 9European Molecular Biology Laboratory (EMBL), Genomics Core Facility, D 69117 Heidelberg, Germany
  • 10European Molecular Biology Laboratory (EMBL), Genome Biology Unit and Molecular Medicine Partnership Unit, D 69117 Heidelberg, Germany
  • 11Institute of Molecular Biology gGmbH, gefördert durch die Böhringer Ingelheim Stiftung, 55128 Mainz, Germany

* * Equal contribution

Received: September 24, 2015Accepted: October 30, 2015Published: November 6, 2015
https://doi.org/10.18632/aging.100835

Copyright: © 2015 Stockklausner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.