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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Article number107328
JournaliScience
Volume26
Issue number8
DOIs
StatePublished - 18 Aug 2023

Keywords

  • Computational molecular modelling
  • Disease
  • Experimental systems for structural biology

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