PU.1 supports TRAIL-induced cell death by inhibiting NF-κB-mediated cell survival and inducing DR5 expression

Cell Death Differ. 2017 May;24(5):866-877. doi: 10.1038/cdd.2017.40. Epub 2017 Mar 31.


The hematopoietic Ets-domain transcription factor PU.1/SPI1 orchestrates myeloid, B- and T-cell development, and also supports hematopoietic stem cell maintenance. Although PU.1 is a renowned tumor suppressor in acute myeloid leukemia (AML), a disease characterized by an accumulation of immature blast cells, comprehensive studies analyzing the role of PU.1 during cell death responses in AML treatment are missing. Modulating PU.1 expression in AML cells, we found that PU.1 supports tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via two mechanisms: (a) by repressing NF-κB activity via a novel direct PU.1-RelA/p65 protein-protein interaction, and (b) by directly inducing TRAIL receptor DR5 expression. Thus, expression of NF-κB-regulated antiapoptotic genes was sustained in PU.1-depleted AML cells upon TRAIL treatment and DR5 levels were decreased. Last, PU.1 deficiency significantly increased AML cell resistance to anthracycline treatment. Altogether, these results reveal a new facet of PU.1's tumor suppressor function during antileukemic therapies.

Publication types

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

MeSH terms

  • Anthracyclines / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Leukemic*
  • HL-60 Cells
  • Humans
  • Protein Binding
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Signal Transduction
  • TNF-Related Apoptosis-Inducing Ligand / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / deficiency
  • Trans-Activators / genetics*
  • Transcription Factor RelA / genetics*
  • Transcription Factor RelA / metabolism


  • Anthracyclines
  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Trans-Activators
  • Transcription Factor RelA
  • proto-oncogene protein Spi-1