Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFκB signaling

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...

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Bibliographic Details
Published in:Leukemia 2019-08, Vol.33 (8), p.1978-1995
Main Authors: Fisher, Daniel A C, Miner, Cathrine A, Engle, Elizabeth K, Hu, Hengrui, Collins, Taylor B, Zhou, Amy, Allen, Maggie J, Malkova, Olga N, Oh, Stephen T
Format: Article
Language:English
Subjects:
Blood cells
Cytokines
Cytokines - biosynthesis
Cytometry
Humans
Hypersensitivity
Immune system
Inflammation
Inhibition
Interleukin 10
Interleukin 6
Interleukin 8
Janus kinase 2
Janus Kinases - physiology
Kinases
MAP kinase
MAP Kinase Signaling System - drug effects
MAP Kinase Signaling System - physiology
Monocytes
Monocytes - immunology
Myelofibrosis
NF-kappa B - antagonists & inhibitors
NF-kappa B - physiology
NF-κB protein
Optimal control
Pathophysiology
Patients
Primary Myelofibrosis - drug therapy
Primary Myelofibrosis - immunology
Progenitor cells
Proteins
Pyrazoles - therapeutic use
Signal Transduction - physiology
Signaling
STAT Transcription Factors - physiology
Stem cells
Thrombopoietin
Thrombopoietin - pharmacology
Toll-like receptors
Toll-Like Receptors - physiology
Tumor necrosis factor
Tumor necrosis factor-TNF
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Summary: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.
ISSN:0887-6924
1476-5551
1476-5551
DOI:10.1038/s41375-019-0379-y