Functional dominance of CHIP-mutated hematopoietic stem cells in patients undergoing autologous transplantation

Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cel
Clonal hematopoiesis of indeterminate potential (CHIP) is caused by recurrent somatic mutations leading to clonal blood cell expansion. However, direct evidence of the fitness of CHIP-mutated human hematopoietic stem cells (HSCs) in blood reconstitution is lacking. Because myeloablative treatment and transplantation enforce stress on HSCs, we followed 81 patients with solid tumors or lymphoid diseases undergoing autologous stem cell transplantation (ASCT) for the development of CHIP. We found a high incidence of CHIP (22%) after ASCT with a high mean variant allele frequency (VAF) of 10.7%. Most mutations were already present in the graft, albeit at lower VAFs, demonstrating a selective reconstitution advantage of mutated HSCs after ASCT. However, patients with CHIP mutations in DNA-damage response genes showed delayed neutrophil reconstitution. Thus, CHIP-mutated stem and progenitor cells largely gain on clone size upon ASCT-related blood reconstitution, leading to an increased future risk of CHIP-associated complications.
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Metadaten
Author:Christina Ann Ortmann, Lena Dorsheimer, Khalil Abou-El-Ardat, Jennifer Hoffrichter, Birgit Aßmus, Halvard-Björn Bönig, Anica Scholz, Heike Pfeifer, Hans Martin, Tobias Schmid, Bernhard Brüne, Sebastian Scheich, Björn Steffen, Julia Riemann, Stella Hermann, Alexandra Dukat, Gesine Bug, Christian Hubertus Brandts, Sebastian Wagner, Hubert Serve, Michael A. Rieger
URN:urn:nbn:de:hebis:30:3-503316
DOI:http://dx.doi.org/10.1016/j.celrep.2019.04.064
ISSN:2211-1247
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=31091442
Parent Title (English):Cell reports
Publisher:Cell Press ; Elsevier
Place of publication:Maryland Heights, MO ; [New York, NY]
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/05/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/05/27
Tag:ASCT; CHIP; autologous stem cell transplantation; chemotherapy; clonal dominance; clonal hematopoiesis; hematopoietic stem cells; hematopoietic stress; leukemia; somatic mutations
Volume:27
Issue:7
Pagenumber:11
First Page:2022
Last Page:2028.e3
Note:
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
HeBIS PPN:450824527
Institutes:Medizin
Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0

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