Bone Marrow Soluble Mediator Signatures of Patients with MPNs

Abstract:

Background:  Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are clonal hematological diseases classified as Philadelphia chromosome-negative myeloproliferative neoplasms (MPN).  MPN pathogenesis is associated with the presence of somatic driver mutations, bone marrow (BM) niche alterations, and tumor inflammatory status.  The relevance of soluble mediators in the pathogenesis of MPN led us to analyze the levels of cytokines, chemokines, and growth factors related to inflammation, angiogenesis and hematopoiesis regulation in the BM niche of MPN patients.

Methods Soluble mediator levels in BM plasma samples from 17 healthy subjects, 28 ET, 19 PV, and 16 PMF patients were determined using a multiplex assay.  Soluble mediator signatures were created from categorical analyses of high mediator producers. Soluble mediator connections and the correlation between plasma levels and clinic-laboratory parameters were also analyzed.

Results:  The soluble mediator signatures of the BM niche of PV patients revealed a highly inflammatory and pro-angiogenic milieu, with increased levels of chemokines (CCL2, CCL5, CXCL8, CXCL12, CXCL10), and growth factors (GM-CSF M-CSF, HGF, IFN-γ, IL-1β, IL-6Ra, IL-12, IL-17, IL-18, TNF-α, VEGF, and VEGF-R2).  ET and PMF patients presented intermediate inflammatory and pro-angiogenic profiles.  Deregulation of soluble mediators was associated with some clinic-laboratory parameters of MPN patients, including vascular events, treatment status, risk stratification of disease, hemoglobin concentration, hematocrit, and red blood cell count.

Conclusions:  Each MPN subtype exhibits a distinct soluble mediator signature.  Deregulated production of BM soluble mediators may contribute to MPN pathogenesis and BM niche modification, provides pro-tumor stimuli, and is a potential target for future therapies.