Circulating cell free mRNA (cf‐mRNA) holds great promise as a non‐invasive diagnostic biomarker.
However, the biological origin of cf‐mRNA is still not well understood, limiting the clinical
applications of this technology. Here, we use the bone marrow (BM) and pharmacologic
manipulation of its resident cells as a window to study the origin of cf‐mRNA. Using NGS‐based
profiling, we show that cf‐mRNA is enriched in transcripts derived from the BM compared to
circulating cells. Further, BM ablation experiments followed by hematopoietic stem cell
transplants in cancer patients show that cf‐mRNA levels reflect the transcriptional activity of BM
resident hematopoietic lineages during marrow reconstitution. Finally, by stimulating specific BM
cell populations in vivo using growth factor therapeutics (i.e. EPO, G‐CSF), we show that cf‐mRNA
reveals dynamic functional changes in growing cell types, suggesting that, unlike other cell‐free
nucleic acids, cf‐mRNA is secreted from living cells, rather than exclusively from apoptotic cells.
Our results shed new light on the biology of cf‐mRNA and demonstrate its potential applications
in clinical practice. Less...