Stromal Cell Senescence Augments Hematopoietic Cell Fitness in Clonal Hematopoiesis

Non-cell-autonomous mechanisms impact tumor growth and metastasis, including remodeling of the tissue microenvironment. The extent to which remodeling of the microenvironment 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 hematopoiesis, we identify subsets of mesenchymal stromal cells (MSCs) in a molecular state of cellular senescence. Using in vivo and ex vivo approaches, we find MSC senescence is induced by Dnmt3a-mutant hematopoietic cells in a cell contact-independent manner through soluble factors, including the cytokines IL-6 and TNF. Mechanistically, these cytokines activate a STAT3-driven senescence induction pathway selectively in MSCs and not in endothelial cells, underscoring cell context specificity. Depletion of senescent MSCs using genetic or pharmacological methods reduces the fitness of Dnmt3a-mutant hematopoietic stem and progenitor cells, and delays development of myeloproliferation which is a precursor to myeloid malignancy. Together, our work identifies that remodeling of the tissue microenvironment modifies pre-malignant clonal fitness and suggests disruption of the crosstalk between pre-malignant cells and their niche as a cancer prevention strategy.