Prefibrotic bone marrow microenvironment is a hallmark of clonal hematopoiesis
TL;DR
F fibro-inflammatory BM remodeling is established 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.
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. Patients with CHIP (clonal hematopoiesis of indeterminate potential) exhibit an abnormal bone marrow environment, which might contribute to malignant development and progression. Multiomic analyses of the bone marrow microenvironment by Tikhonova and colleagues reveal an inflammatory–fibrotic link between immune cells and altered bone marrow-resident fibroblasts.