# Non-invasive detection of bone marrow fibrosis in myeloproliferative neoplasms using cell-free RNA

## TL;DR

This paper shows that cell-free RNA from blood can detect bone marrow fibrosis in myeloproliferative neoplasms, identifying key drivers like RUNX1 and IL-18.

## Contribution

The study introduces a non-invasive method using cf-RNA to detect and stratify bone marrow fibrosis in MPNs.

## Key findings

- Peripheral cf-RNA profiling correlates with reticulin fibrosis grades and reveals TGF-β and ECM changes.
- RUNX1 overexpression drives myofibroblast differentiation in mesenchymal stromal cells.
- IL-18 is a critical mediator of fibrosis and marks the transition to advanced disease stages.

## Abstract

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 the peripheral blood of patients with MPN (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 extracellular matrix (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-grade fibrosis (reticulin grades 2–3). Functional assays confirmed that the IL-18 stimulation of mesenchymal stromal cells induced fibrotic transformation, emphasizing its role as a biomarker and target.

•Peripheral cf-RNA profiling stratifies bone marrow fibrosis in patients with MPN•RUNX1 drives stromal myofibroblast transformation•IL-18 drives marrow fibrosis and marks transition to advanced disease stage

Peripheral cf-RNA profiling stratifies bone marrow fibrosis in patients with MPN

RUNX1 drives stromal myofibroblast transformation

IL-18 drives marrow fibrosis and marks transition to advanced disease stage

Myelofibrosis; Cell-free RNA; Inflammation; Hematopoiesis; Cancer