Non-Invasive Detection of Bone Marrow Fibrosis in Myeloproliferative Neoplasms Using Cell-Free RNA

Myeloproliferative neoplasms (MPNs), particularly with myelofibrosis (MF), involve a disrupted perivascular hematopoietic niche ultimately leading to bone marrow fibrosis. We asked if the transcriptome in cell-free RNA (cf-RNA) from peripheral blood of MPN patients (with JAK2V617F mutation) can detect bone marrow fibrosis. Transcriptomic profiling revealed significant gene expression changes correlating with reticulin fibrosis grades. Advanced reticulin fibrosis grades (2-3) showed upregulation of TGF-β pathways and ECM remodeling markers, with decreased hematopoietic support. Grade 3 fibrosis was associated with increased proliferation signals and elevated inflammatory markers (S100A8/9). RUNX1 was identified as a key transcription factor in fibrosis with its overexpression driving myofibroblast differentiation in mesenchymal stromal cells. IL-18 emerged as a critical inflammatory mediator, with elevated plasma levels correlating with the transformation to high grades fibrosis (reticulin grades 2-3). Functional assays confirmed that IL-18 stimulation of mesenchymal stromal cells induced fibrotic transformation, emphasizing its role as a biomarker and target.