Document Type

Article

Publication Date

8-1-2026

Keywords

JMG, Animals, Cellular Senescence, Humans, DNA Methyltransferase 3A, DNA (Cytosine-5-)-Methyltransferases, Mesenchymal Stem Cells, Tumor Necrosis Factor-alpha, STAT3 Transcription Factor, Clonal Hematopoiesis, Hematopoietic Stem Cells, Mice, Interleukin-6, Mutation, Signal Transduction, Hematopoiesis, Mice, Inbred C57BL, Female

JAX Source

Nat Cell Biol. 2026 Aug;28(8):1656-70.

ISSN

1476-4679

PMID

42562925

DOI

https://doi.org/10.1038/s41556-026-02025-4

Grant

This work was supported by NIH grant nos. R01DK118072 and R01AG069010, an EvansMDS Discovery Research Grant to J.J.T., and U01AG077925 to J.J.T. and R.L.L. This work was supported in part by NIH/NCI Cancer Centre Support Grant P30CA034196. Work in the Levine laboratory is supported by MSKCC Support Grant/Core Grant P30CA008748. J.J.T. was supported by a Blood Cancer United (formerly Leukemia & Lymphoma Society) Scholar Award, Scholar Achievement Award and The Dattels Family Endowed Chair. J.J.M. was supported by a Blood Cancer United Career Development Program Fellow Award and The Jackson Laboratory Scholar Award.

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.

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