An inflammatory T-cell-stromal axis contributes to hematopoietic stem/progenitor cell failure and clonal evolution in human myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is characterized by bone marrow failure, clonal evolution and leukemic progression, but the pathophysiologic processes driving these events remain incompletely understood. Here, by establishing a comprehensive single-cell transcriptional taxonomy of human MDS, we revea...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 16; no. 1; pp. 10041 - 22
Main Authors: Chen, Lanpeng, Bian, Yujie, Pronk, Eline, van Dijk, Claire, V.D. van Tienhoven, Tim, Hoogenboezem, Remco M., Bindels, Eric M., Bosch, Dennis, Fazeli, Sadaf, de Graaf, Aniek O., Westers, Theresia M., Kholmatov, Maksim, Zaugg, Judith B., Moura, Pedro L., Hellström-Lindberg, Eva, van de Loosdrecht, Arjan A., Jansen, Joop H., Sanders, Mathijs A., Raaijmakers, Marc H.G.P.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 18.11.2025
Nature Publishing Group
Nature Portfolio
Subjects:
13/1
13/100
13/106
13/109
13/31
14/19
14/34
14/63
38
38/109
38/39
38/77
38/90
38/91
42
45
49
49/31
631/250/1619/554/1834
631/532/1542
631/67/1990/1673
631/67/327
64/60
Animals
Apoptosis
Biological evolution
Bone marrow
Bone remodeling
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Clonal Evolution - genetics
Clonal Evolution - immunology
Clonal selection
Cloning
Competitive advantage
Datasets
Evolution
Failure
Female
Gene expression
Hematopoietic stem cells
Hematopoietic Stem Cells - immunology
Hematopoietic Stem Cells - metabolism
Hematopoietic Stem Cells - pathology
Hematopoietic system
Hemopoiesis
Humanities and Social Sciences
Humans
Inflammation
Inflammation - immunology
Inflammation - pathology
Leukemia
Lymphocytes T
Male
Mice
multidisciplinary
Mutation
Myelodysplastic syndrome
Myelodysplastic syndromes
Myelodysplastic Syndromes - genetics
Myelodysplastic Syndromes - immunology
Myelodysplastic Syndromes - pathology
Neoplasms
Pathogenesis
Progenitor cells
Science
Science (multidisciplinary)
Signal Transduction
Stem Cell Niche - immunology
Stem cells
Stromal Cells
Taxonomy
ISSN:2041-1723, 2041-1723
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Myelodysplastic syndrome (MDS) is characterized by bone marrow failure, clonal evolution and leukemic progression, but the pathophysiologic processes driving these events remain incompletely understood. Here, by establishing a comprehensive single-cell transcriptional taxonomy of human MDS, we reveal that inflammatory remodeling of bone marrow stromal niches is a common early feature, irrespective of the genetic driver landscape. We identify an activated CD8-T-cell subset as a source of stromal inflammation via TNF-receptor signaling, which prompts the inflammatory rewiring and loss of repopulating ability of residual normal hematopoietic stem/progenitor cells (HSPC). Mutant HSPCs display relative resistance to this inflammatory stress and reside predominantly in a transcriptional ‘high output’ state, providing a biological framework to their competitive advantage in an inflammatory microenvironment. Consistent with this, stromal inflammation associates with leukemic progression and reduced survival. Our data thus support a model of immune-stromal inflammatory signaling driving tissue failure and clonal evolution in the hematopoietic system. Mechanisms of clonal evolution in myeloid neoplasms remain incompletely understood. Darwinian theory predicts that the (micro)environment of clone-propagating stem cells may contribute to clonal selection. Here, we provide data fitting this model, establishing a relationship between stromal niche inflammation, inflammatory stress in HSPCs, clonal resistance and leukemic evolution in human MDS. Mechanisms of clonal evolution in myeloid neoplasms remain incompletely understood. Darwinian theory predicts that the (micro)environment of clone-propagating stem cells may contribute to clonal selection. Here, authors provide data fitting this model, establishing a relationship between stromal niche inflammation, inflammatory stress in HSPCs, clonal resistance and leukemic evolution in human myelodysplastic syndrome.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-65802-z