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Buck, M.C.* ; Bast, L. ; Hecker, J.S.* ; Riviere, J.* ; Rothenberg-Thurley, M.* ; Vogel, L.* ; Wang, D. ; Andrä, I.* ; Theis, F.J. ; Bassermann, F.* ; Metzeler, K.H.* ; Oostendorp, R.A.J.* ; Marr, C. ; Götze, K.S.*

Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS.

iScience 26:107328 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Clonal hematopoiesis of indeterminate potential (CHIP) describes the age-related acquisition of somatic mutations in hematopoietic stem/progenitor cells (HSPC) leading to clonal blood cell expansion. Although CHIP mutations drive myeloid malignancies like myelodysplastic syndromes (MDS) it is unknown if clonal expansion is attributable to changes in cell type kinetics, or involves reorganization of the hematopoietic hierarchy. Using computational modeling we analyzed differentiation and proliferation kinetics of cultured hematopoietic stem cells (HSC) from 8 healthy individuals, 7 CHIP, and 10 MDS patients. While the standard hematopoietic hierarchy explained HSPC kinetics in healthy samples, 57% of CHIP and 70% of MDS samples were best described with alternative hierarchies. Deregulated kinetics were found at various HSPC compartments with high inter-individual heterogeneity in CHIP and MDS, while altered HSC rates were most relevant in MDS. Quantifying kinetic heterogeneity in detail, we show that reorganization of the HSPC compartment is already detectable in the premalignant CHIP state.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Computational Molecular Modelling ; Disease ; Experimental Systems For Structural Biology; Stem-cells; Myelodysplastic Syndromes; Progenitor; Risk; Differentiation; Hierarchy; Landscape
ISSN (print) / ISBN 2589-0042
e-ISSN 2589-0042
Zeitschrift iScience
Quellenangaben Band: 26, Heft: 8, Seiten: , Artikelnummer: 107328 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam ; Bosten ; London ; New York ; Oxford ; Paris ; Philadelphia ; San Diego ; St. Louis
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
Institute of AI for Health (AIH)
Förderungen Marie Curie Actions (MSCA)
Joachim Herz Stiftung
ERC under the European Union
BMBF
European Research Council (ERC) under the European Union
German Cancer Consortium joint funding program (DKTK CHOICE)
Deutsche Jose Carreras Leukamie Stiftung (DJCLS)
Deutsche Forschungsgemeinschaft