Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFκB signaling.
Daniel A C FisherCathrine A MinerElizabeth K EngleHengrui HuTaylor B CollinsAmy ZhouMaggie J AllenOlga N MalkovaStephen T OhPublished in: Leukemia (2019)
The distinct clinical features of myelofibrosis (MF) have been attributed in part to dysregulated inflammatory cytokine production. Circulating cytokine levels are elevated in MF patients; a subset of which have been shown to be poor prognostic indicators. In this study, cytokine overproduction was examined in MF patient plasma and in MF blood cells ex vivo using mass cytometry. Plasma cytokines measured following treatment with ruxolitinib remained markedly abnormal, indicating that aberrant cytokine production persists despite therapeutic JAK2 inhibition. In MF patient samples, 14/15 cytokines measured by mass cytometry were found to be constitutively overproduced, with the principal cellular source for most cytokines being monocytes, implicating a non-cell-autonomous role for monocyte-derived cytokines impacting disease-propagating stem/progenitor cells in MF. The majority of cytokines elevated in MF exhibited ex vivo hypersensitivity to thrombopoietin (TPO), toll-like receptor (TLR) ligands, and/or tumor necrosis factor (TNF). A subset of this group (including TNF, IL-6, IL-8, IL-10) was minimally sensitive to ruxolitinib. All TPO/TLR/TNF-sensitive cytokines, however, were sensitive to pharmacologic inhibition of NFκB and/or MAP kinase signaling. These results indicate that NFκB and MAP kinase signaling maintain cytokine overproduction in MF, and that inhibition of these pathways may provide optimal control of inflammatory pathophysiology in MF.
Keyphrases
- toll like receptor
- nuclear factor
- inflammatory response
- rheumatoid arthritis
- oxidative stress
- signaling pathway
- single cell
- lps induced
- immune response
- end stage renal disease
- case report
- induced apoptosis
- dendritic cells
- pi k akt
- chronic kidney disease
- stem cells
- ejection fraction
- protein kinase
- prognostic factors
- tyrosine kinase
- high density
- cell cycle arrest
- mesenchymal stem cells
- peritoneal dialysis
- peripheral blood
- patient reported outcomes