Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS
Michèle C. Buck,
Lisa Bast,
Judith S. Hecker,
Jennifer Rivière,
Maja Rothenberg-Thurley,
Luisa Vogel,
Dantong Wang,
Immanuel Andrä,
Fabian J. Theis,
Florian Bassermann,
Klaus H. Metzeler,
Robert A.J. Oostendorp,
Carsten Marr,
Katharina S. Götze
Affiliations
Michèle C. Buck
Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany
Lisa Bast
Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany; Technical University of Munich (TUM), Department of Mathematics, Chair of Mathematical Modeling of Biological Systems, Garching, Germany
Judith S. Hecker
Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany
Jennifer Rivière
Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany
Maja Rothenberg-Thurley
University Hospital, Ludwig-Maximilians-University, Department of Medicine III, Laboratory for Leukemia Diagnostics, Munich, Germany
Luisa Vogel
Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany
Dantong Wang
Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany; Technical University of Munich (TUM), Department of Mathematics, Chair of Mathematical Modeling of Biological Systems, Garching, Germany
Immanuel Andrä
Technical University of Munich, Microbiology Institute, Munich, Germany
Fabian J. Theis
Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany; Technical University of Munich (TUM), Department of Mathematics, Chair of Mathematical Modeling of Biological Systems, Garching, Germany
Florian Bassermann
Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Partner Site Munich, Germany
Klaus H. Metzeler
University Hospital, Ludwig-Maximilians-University, Department of Medicine III, Laboratory for Leukemia Diagnostics, Munich, Germany; University Hospital Leipzig, Department of Hematology and Cell Therapy, Leipzig, Germany
Robert A.J. Oostendorp
Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany
Carsten Marr
Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Partner Site Munich, Germany; Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of AI for Health, Neuherberg, Germany; Corresponding author
Katharina S. Götze
Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Partner Site Munich, Germany; Corresponding author
Summary: 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.
