Prefibrotic bone marrow microenvironment is a hallmark of clonal hematopoiesis

Abstract

Clonal hematopoiesis of indeterminate potential is associated with systemic inflammation and increased malignant risk in humans, yet understanding of how it reshapes the bone marrow (BM) microenvironment has been limited. Using single-cell transcriptomic profiling of freshly isolated BM samples, combined with histological and spatial transcriptomic analyses, we identified fibro-inflammatory remodeling as a hallmark of clonal hematopoiesis of indeterminate potential. Fibroblasts were markedly expanded and acquired cancer-associated fibroblast-like transcriptional states, while mesenchymal and vascular cells upregulated collagen production and extracellular matrix remodeling pathways. Spatial transcriptomics revealed discrete fiber-enriched regions populated by active and CXCL12+ fibroblasts, macrophages and lymphoid cells. These regions exhibited major enrichment of proinflammatory pathways, including transforming growth factor-beta and tumor necrosis factor signaling, identifying them as spatially confined inflammatory hubs within the BM. Collectively, these findings establish fibro-inflammatory BM remodeling as a defining feature of clonal hematopoiesis of indeterminate potential, linking it to prefibrotic stromal changes and niche reorganization that may facilitate progression to overt malignancy.