Prefibrotic Bone Marrow Microenvironment is a Hallmark of Clonal Hematopoiesis

Clonal hematopoiesis of indeterminate potential (CHIP) is linked to systemic inflammation and increased malignant risk, yet its impact on the bone marrow (BM) niche remains poorly understood. Through single-cell transcriptomic profiling of freshly isolated BM, we identify fibro-inflammatory rewiring as an early hallmark of CHIP. Beyond a myeloid-biased inflammatory state, CHIP BM exhibited coordinated TNFα activation across hematopoietic progenitor, monocyte, and stromal compartments. Stromal populations displayed early fibrotic remodeling, with mesenchymal and vascular cells upregulating collagen and extracellular matrix programs. Fibroblasts were markedly expanded independent of mutational subtype and acquired cancer-associated fibroblast (CAF)-like programs, rewiring niche interactions through IL-6, TGFβ, and collagen-integrin signaling. Together, these findings establish fibro-inflammatory BM remodeling as an early hallmark of clonal expansion, linking CHIP to prefibrotic stromal remodeling, immune dysregulation, and a niche architecture consistent with increased malignant risk.

• Type: Transcriptome Sequencing
• Archive: European Genome-phenome Archive (EGA)