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Published on: May 15, 2019

PU.1 induces apoptosis in myeloma cells through direct transactivation of TRAIL

S Ueno1, H Tatetsu, H Hata

  • 1Department of Hematology, Kumamoto University of Medicine, Kumamoto 860-8556, Japan.

Oncogene
|September 15, 2009
PubMed

Insights

The transcription factor PU.1 induces myeloma cell death by directly activating the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) gene, offering a potential therapeutic target for multiple myeloma.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • PU.1, a transcription factor, is downregulated in a subset of multiple myeloma patients and cell lines.
  • PU.1 expression can induce growth arrest and apoptosis in PU.1-negative myeloma cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which PU.1 induces apoptosis in myeloma cells.
  • To investigate the role of specific genes, including apoptosis-related genes, in PU.1-mediated effects.

Main Methods:

  • DNA microarray analysis to compare gene expression profiles before and after PU.1 induction.
  • Small interfering RNA (siRNA) knockdown of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL).
  • Reporter assays to assess PU.1 transactivation of the TRAIL promoter and chromatin immunoprecipitation (ChIP) to confirm direct binding.

Main Results:

  • PU.1 induction led to downregulation of cell cycle genes (cyclin A2, B1, CDK2, CDK4) and upregulation of p21.
  • Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was significantly upregulated following PU.1 induction.
  • Knockdown of TRAIL inhibited PU.1-induced apoptosis, indicating TRAIL's critical role.
  • PU.1 directly binds to the TRAIL gene promoter and transactivates its expression.

Conclusions:

  • PU.1 induces apoptosis in certain myeloma cells through direct transactivation of the TRAIL gene.
  • TRAIL is a key mediator of PU.1-induced apoptosis in multiple myeloma.
  • Targeting PU.1 or TRAIL may represent a novel therapeutic strategy for multiple myeloma.

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