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

Autoren

Clemens Stockklausner
Simon Raffel
Julia Klermund
Obul Reddy Bandapalli
Fabian Beier
Tim H Brümmendorf
Friederike Bürger
Sven W Sauer
Georg F Hoffmann
Holger Lorenz
Laura Tagliaferri
Daniel Nowak
Wolf-Karsten Hofmann
Rebecca Buergermeister
Carolin Kerber
Tobias Rausch
Jan O Korbel
Brian Luke
Andreas Trumpp
Andreas E Kulozik

DOI

10.18632/aging.100835

eISSN

1945-4589

Ausgabe der Veröffentlichung

11

Zeitschrift

Aging

Sprache

en

Online publication date

2015

Paginierung

911 - 927

Datum der Veröffentlichung

2015

Status

Published

Herausgeber

Impact Journals, LLC

Herausgeber URL

http://dx.doi.org/10.18632/aging.100835

Datum der Datenerfassung

2020

Titel

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

Ausgabe der Zeitschrift

7

Datenquelle: Crossref

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.

Addresses

Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg and Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany.

Autoren

Clemens Stockklausner
Simon Raffel
Julia Klermund
Obul Reddy Bandapalli
Fabian Beier
Tim H Brümmendorf
Friederike Bürger
Sven W Sauer
Georg F Hoffmann
Holger Lorenz
Laura Tagliaferri
Daniel Nowak
Wolf-Karsten Hofmann
Rebecca Buergermeister
Carolin Kerber
Tobias Rausch
Jan O Korbel
Brian Luke
Andreas Trumpp
Andreas E Kulozik

DOI

10.18632/aging.100835

eISSN

1945-4589

Externe Identifier

PubMed Identifier: 26546739
PubMed Central ID: PMC4694062

Open access

true

ISSN

1945-4589

Ausgabe der Veröffentlichung

11

Zeitschrift

Aging

Schlüsselwörter

Hematopoietic Stem Cells
Hela Cells
Telomere
Animals
Humans
Mice
Dyskeratosis Congenita
Sirolimus
Telomerase
Antigens, CD34
Hematopoietic Stem Cell Transplantation
Mutation
Female
TOR Serine-Threonine Kinases
Cellular Senescence

Sprache

eng

Medium

Print

Open access status

Open Access

Paginierung

911 - 927

Datum der Veröffentlichung

2015

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2015

Titel

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.

Sub types

Research Support, Non-U.S. Gov't
research-article
Journal Article

Ausgabe der Zeitschrift

7

Files

https://europepmc.org/articles/PMC4694062?pdf=render

Datenquelle: Europe PubMed Central

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.

Autoren

Clemens Stockklausner
Simon Raffel
Julia Klermund
Obul Reddy Bandapalli
Fabian Beier
Tim H Brümmendorf
Friederike Bürger
Sven W Sauer
Georg F Hoffmann
Holger Lorenz
Laura Tagliaferri
Daniel Nowak
Wolf-Karsten Hofmann
Rebecca Buergermeister
Carolin Kerber
Tobias Rausch
Jan O Korbel
Brian Luke
Andreas Trumpp
Andreas E Kulozik

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/26546739

DOI

10.18632/aging.100835

eISSN

1945-4589

Externe Identifier

PubMed Central ID: PMC4694062

Ausgabe der Veröffentlichung

11

Zeitschrift

Aging (Albany NY)

Schlüsselwörter

TERC
TERT
mTOR
rapamycin
senescence
sirolimus
Animals
Antigens, CD34
Cellular Senescence
Dyskeratosis Congenita
Female
HeLa Cells
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Humans
Mice
Mutation
Sirolimus
TOR Serine-Threonine Kinases
Telomerase
Telomere

Sprache

eng

Country

United States

Paginierung

911 - 927

PII

100835

Datum der Veröffentlichung

2015

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2016

Titel

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.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

7

Datenquelle: PubMed

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.

Autoren

Clemens Stockklausner
Simon Raffel
Julia Klermund
Obul Reddy Bandapalli
Fabian Beier
Tim H Brümmendorf
Friederike Bürger
Sven W Sauer
Georg F Hoffmann
Holger Lorenz
Laura Tagliaferri
Daniel Nowak
Wolf-Karsten Hofmann
Rebecca Buergermeister
Carolin Kerber
Tobias Rausch
Jan O Korbel
Brian Luke
Andreas Trumpp
Andreas E Kulozik

DOI

10.18632/aging.100835

Zeitschrift

Aging

Notes

keywords: Animals;Antigens, CD34/analysis;Cellular Senescence;Dyskeratosis Congenita/genetics;Female;HeLa Cells;Hematopoietic Stem Cell Transplantation;Hematopoietic Stem Cells/physiology;Humans;Mice;Mutation;Sirolimus/pharmacology;Telomerase/genetics;Telomere;TOR Serine-Threonine Kinases/antagonists & inhibitors

Artikelnummer

11

Paginierung

911 - 927

Datum der Veröffentlichung

2015

Datum der Datenerfassung

2023

Titel

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

Sub types

article

Ausgabe der Zeitschrift

7

Datenquelle: Manual

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

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