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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)

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Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords 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

Journal iScience

Quellenangaben Volume: 26, Issue: 8, Article Number: 107328

Publisher Elsevier

Publishing Place Amsterdam ; Bosten ; London ; New York ; Oxford ; Paris ; Philadelphia ; San Diego ; St. Louis

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)
Institute of AI for Health (AIH)

Grants 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