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

Lanpeng Chen, Yujie Bian, Eline Pronk, Claire van Dijk, Tim V.D. van Tienhoven, Remco M. Hoogenboezem, Eric M. Bindels, Dennis Bosch, Sadaf Fazeli, Aniek O. de Graaf, Theresia M. Westers, Maksim Kholmatov, Judith B. Zaugg, Pedro L. Moura, Eva Hellström-Lindberg, Arjan A. van de Loosdrecht, Joop H. Jansen, Mathijs A. Sanders and Marc H.G.P. Raaijmakers ()
Additional contact information
Lanpeng Chen: Erasmus MC Cancer Institute
Yujie Bian: Erasmus MC Cancer Institute
Eline Pronk: Erasmus MC Cancer Institute
Claire van Dijk: Erasmus MC Cancer Institute
Tim V.D. van Tienhoven: Erasmus MC Cancer Institute
Remco M. Hoogenboezem: Erasmus MC Cancer Institute
Eric M. Bindels: Erasmus MC Cancer Institute
Dennis Bosch: Erasmus MC Cancer Institute
Sadaf Fazeli: Karolinska Institute
Aniek O. de Graaf: Radboud UMC
Theresia M. Westers: Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam
Maksim Kholmatov: European Molecular Biology Laboratory, Structural and Computational Biology Unit
Judith B. Zaugg: European Molecular Biology Laboratory, Structural and Computational Biology Unit
Pedro L. Moura: Karolinska Institute
Eva Hellström-Lindberg: Karolinska Institute
Arjan A. van de Loosdrecht: Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam
Joop H. Jansen: Radboud UMC
Mathijs A. Sanders: Erasmus MC Cancer Institute
Marc H.G.P. Raaijmakers: Erasmus MC Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65802-z

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