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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
07:09

Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity

Published on: January 7, 2019

PML mediates IFN-alpha-induced apoptosis in myeloma by regulating TRAIL induction

Chun Crowder1, Øyvind Dahle, R Eric Davis

  • 1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Blood
|October 2, 2004
PubMed

Insights

Interferon (IFN) treatment

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Interferon (IFN) is used clinically for multiple myeloma and induces proapoptotic genes.
  • The promyelocytic leukemia (PML) gene, an IFN target, encodes a tumor suppressor protein found in PML nuclear bodies (NBs).
  • Mechanisms underlying differential responses of multiple myeloma cells to IFN are not fully understood.

Purpose of the Study:

  • To investigate the roles of PML nuclear bodies (NBs) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in IFN-alpha-induced apoptosis in multiple myeloma.
  • To identify downstream targets of PML involved in IFN-alpha-mediated anti-myeloma effects.

Main Methods:

  • Correlated IFN-alpha-induced growth inhibition with PML NBs and TRAIL expression in myeloma cells.
  • Utilized RNA interference (RNAi) to silence PML expression.
  • Assessed the effect of dominant-negative TRAIL receptor (DR5) expression on IFN-induced cell death.

Main Results:

  • IFN-alpha's growth inhibition in myeloma cells correlated with PML NBs and TRAIL induction, not with known IFN targets like STAT1, STAT3, p38, or Daxx.
  • PML silencing abrogated IFN-alpha-induced apoptosis and reduced TRAIL expression.
  • Expression of a dominant-negative TRAIL receptor partially inhibited IFN-induced myeloma cell death.

Conclusions:

  • PML and TRAIL are critical effectors of IFN-alpha-induced apoptosis in multiple myeloma.
  • TRAIL is identified as a novel downstream transcriptional target of PML.
  • Understanding PML and PML NBs' roles offers insights into IFN resistance mechanisms in tumor cells and aids in treatment assessment.

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