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

Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS

Affiliations

Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS

Michèle C Buck et al. iScience. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Percentages of HSPC are progressively reduced in CHIP and MDS bone marrow (BM) snapshot data (A) Representative BM snapshot analysis of healthy, CHIP, and MDS. For CMP, GMP, and MEP fractions, cells were gated on lin-CD45dimCD34+CD38+ cells and further distinguished using CD123 and CD45RA. For HSC, MPP, and MLP fractions, cells were gated on lin-CD45dimCD34+CD38 cells and further distinguished using CD90 and CD45RA. (B) BM snapshots of healthy, CHIP, and MDS samples reveal a significantly reduced percentage of hematopoietic stem and progenitor cells (HSPC) in all lin- cells in MDS patients (p = 0.038, Kruskal-Wallis test followed by Dunn’s multiple comparison test). Data are represented as individual points of independent samples, lines indicate median. (C) The frequencies of CMP and GMP are significantly reduced in MDS BM (p = 0.0031 for CMP healthy vs. MDS, p = 0.0074 for GMP healthy vs. MDS, p = 0.017 for GMP CHIP vs. MDS, Kruskal-Wallis test followed by Dunn’s multiple comparison test). For all compartments, a trend toward reduced frequencies from healthy over CHIP to MDS can be observed. Data are represented as individual points of independent samples, lines indicate median.
Figure 2
Figure 2
HSC derived from CHIP, MDS, and healthy samples expand and differentiate in 7-day in vitro cultures (A) Workflow for investigating HSC in vitro behavior in healthy (n = 8), CHIP (n = 7), and MDS (n = 10) BM samples. After FACS-sorting of HSC, cells were cultured in serum-free medium allowing differentiation followed by time-resolved measurements of cell number, cell type, and cell division status by FACS. (B) Cell counts of HSC, MPP, MLP, CMP, GMP, MEP, and mature cell compartments during 7-day culture. Individual samples are represented as points along the 7-day period. (C) Cell divisions measured by FACS in all cell types reveal similar patterns in exemplary healthy (H5 and H8) and CHIP (C4 and C5) samples, but hyperproliferation in MDS (sample M6).
Figure 3
Figure 3
Hierarchy heterogeneity and number of deregulated rates increases from clonal hematopoiesis to MDS (A) Mature (CD34) cells from sample M10 which underwent 0 divisions fitted with model A (rejected) and model D (best performing). (B) Systematic model comparison reveals best performing models according to BIC values are model A (5 CHIP and 3 MDS individuals), model B (2 CHIP and 3 MDS individuals), model D (2 MDS individuals), model G (2 MDS individuals) and model I (2 CHIP individuals). For two healthy individuals (H4 and H5), two models perform similarly well. (C) Union of best performing models in at least one healthy, MDS, or CHIP sample defines a new hematopoietic hierarchy model. (D) Detected up-regulated (orange) and down-regulated (blue) rates for each healthy individual. (E) Detected up-regulated (orange) and down-regulated (blue) rates for each CHIP individual. (F) Detected up-regulated (orange) and down-regulated (blue) rates for each MDS individual. (G) A higher number of altered rates per individual can be found in CHIP and MDS.
Figure 4
Figure 4
MDS samples can be distinguished from CHIP and healthy samples using PCA Weighted PCA was performed on proliferation, differentiation, and cell death rates of each cell compartment estimated from MDS patients. Depicted are PC1, PC2, PC3, and PC4. Dots show the location of each sample. Blue ellipses indicate 95% and 85% confidence areas based on rates of healthy donors. (A) Donor samples (dots) with their ID in PCA space spanned by the first four PCs. Highlighted are their disease status (healthy, CHIP, and MDS). (B) Donor samples in PC space with their respective IPSS-R score. (C) Donor samples in PC space with their respective number of mutations.

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