Stromal cell senescence augments haematopoietic cell fitness in clonal haematopoiesis
Year: 2026
Type: article
Abstract: Microenvironment remodelling impacts tumour growth and metastasis, but whether remodelling promotes pre-malignant clonal fitness remains unknown. Here, using single-cell RNA-sequencing of the bone-marrow microenvironment in a mouse model of DNMT3A-mutant clonal haematopoiesis (CH), we identify mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Elevated bone-marrow MSC senescence is also observed in humans with CH driven by several common somatic mutations. MSC senescence is induced by mutant haematopoietic cells in a contact-independent manner through production of soluble factors including TNF-α and IL-6. These cytokines activate a Stat3-driven pathway that is necessary and sufficient for MSC senescence induction. Genetic or pharmacological depletion of senescent non-haematopoietic cells reduces the burden of CH and delays progression to myeloid neoplasia. Our findings show that microenvironment remodelling modifies pre-malignant clonal fitness and identifies disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.
Source: Nature Cell Biology
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Leukemia and Lymphoma Society, Jackson Laboratory, Edward P. Evans Foundation, Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canada Research Chairs, National Institutes of Health, Horizon 2020 Framework Programme, Canadian Institutes of Health Research, National Institute on Aging, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Discovery of Aging-Associated Mechanisms Causing Expansion and Progression of Clonal Hematopoiesis of Indeterminant Potential (CHIP), G2672720727, G278894908, G4237588196, G4841871804, G8417515966, Cancer Center Support Grant, Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation, G915599002
OpenAlex ID: W7196939532