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

Leukemia. 2019 Aug;33(8):1978-1995. doi: 10.1038/s41375-019-0379-y. Epub 2019 Feb 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / biosynthesis*
  • Humans
  • Janus Kinases / physiology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Monocytes / immunology
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Primary Myelofibrosis / drug therapy
  • Primary Myelofibrosis / immunology*
  • Pyrazoles / therapeutic use
  • STAT Transcription Factors / physiology*
  • Signal Transduction / physiology*
  • Thrombopoietin / pharmacology
  • Toll-Like Receptors / physiology

Substances

  • Cytokines
  • INCB018424
  • NF-kappa B
  • Pyrazoles
  • STAT Transcription Factors
  • Toll-Like Receptors
  • Thrombopoietin
  • Janus Kinases