PU.1 supports TRAIL-induced cell death by inhibiting NF-κB-mediated cell survival and inducing DR5 expression.
Aladin HaimoviciMagali HumbertElena A FederzoniDeborah Shan-KrauerThomas BrunnerSteffen FreseThomas KaufmannBruce E TorbettMario P TschanPublished in: Cell death and differentiation (2017)
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.
Keyphrases
- cell cycle arrest
- cell death
- acute myeloid leukemia
- signaling pathway
- induced apoptosis
- pi k akt
- poor prognosis
- transcription factor
- oxidative stress
- protein protein
- endoplasmic reticulum stress
- binding protein
- lps induced
- genome wide
- stem cells
- long non coding rna
- nuclear factor
- immune response
- combination therapy
- dna methylation
- dendritic cells
- high glucose
- toll like receptor
- cell therapy
- acute lymphoblastic leukemia
- endothelial cells
- case control