Bone Marrow Soluble Mediator Signatures of Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Abstract

BackgroundEssential 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.MethodsSoluble 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.ResultsThe 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.ConclusionsEach 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.

Integrated Single-Cell Genotyping and Chromatin Accessibility ChartsJAK2V617FHuman Hematopoietic Differentiation

“…CSF1 can promote differentiation of HSPCs towards the myeloid lineage 65 and CSF2 has been shown to be required for differentiation of precursor cells towards the myeloid/erythroid fate 66 . We also observed increased accessibility of the CCL2 gene, a key cytokine mediating monocyte recruitment to inflammatory sites 67 , which has been reported to be increased in MF 68 .…”

Human bone marrow organoids for disease modelling, discovery and validation of therapeutic targets in hematological malignancies

“…5A), a markers of fibroblast activation(53). A significant increase in soluble IL11 was also observed (54)(Fig. 5B).…”

Philadelfia-negative myeloproliferative neoplasms display alterations in monocyte subpopulations frequency and immunophenotype

“…The pro-in ammatory status seem to contribute to MPN pathophysiology [4,6,8], once the isolated presence of driver mutations are insu cient to fully explain the mechanisms underlying the MPN pathogenesis, progression and phenotypes [27]. Many authors have reported the association of oncoin ammation [6, 7, 8, 27] with genetic instability, symptomatology, endothelial dysfunction and procoagulant state in MPN [9,10,18].…”

“…Beyond the genetic alterations, MPN are considered as oncoin ammatory diseases due to exacerbated in ammatory status [6,7,8]. Recent studies have reported increased levels of pro-in ammatory cytokines, chemokines and growth factors in bone marrow niche and peripheral blood from PV, ET and MF patients [6, 9, 10] and associated them with patients' clinic-laboratory parameters [9,10]. Therefore, the proin ammatory pro le seems to contribute genetic and epigenetic instability, predisposition to cardiovascular events, brotic progression and leukemic transformation in MPN [5,6,11,12].…”