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

doi:10.1016/j.isci.2023.107328

Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS

iScience. 2023 Jul 10;26(8):107328. doi: 10.1016/j.isci.2023.107328. eCollection 2023 Aug 18.

Authors

Michèle C Buck¹, Lisa Bast^{2

3}, Judith S Hecker¹, Jennifer Rivière¹, Maja Rothenberg-Thurley⁴, Luisa Vogel¹, Dantong Wang^{2

3}, Immanuel Andrä⁵, Fabian J Theis^{2

3}, Florian Bassermann^{1

6}, Klaus H Metzeler^{4

7}, Robert A J Oostendorp¹, Carsten Marr^{2

6

8}, Katharina S Götze^{1

6}

Affiliations

¹ Technical University of Munich (TUM), School of Medicine, Department of Medicine III, Munich, Germany.
² Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany.
³ Technical University of Munich (TUM), Department of Mathematics, Chair of Mathematical Modeling of Biological Systems, Garching, Germany.
⁴ University Hospital, Ludwig-Maximilians-University, Department of Medicine III, Laboratory for Leukemia Diagnostics, Munich, Germany.
⁵ Technical University of Munich, Microbiology Institute, Munich, Germany.
⁶ German Cancer Consortium (DKTK), Heidelberg, Partner Site Munich, Germany.
⁷ University Hospital Leipzig, Department of Hematology and Cell Therapy, Leipzig, Germany.
⁸ Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of AI for Health, Neuherberg, Germany.

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.

Keywords: Computational molecular modelling; Disease; Experimental systems for structural biology.