PU.1 supports TRAIL-induced cell death by inhibiting NF-κB-mediated cell survival and inducing DR5 expression.
Publisher DOI
PubMed ID
28362429
Abstract
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.Cell Death and Differentiation advance online publication, 31 March 2017; doi:10.1038/cdd.2017.40.
Date Issued
2017-03-31
Publication Type
Article
Language(s)
en
Author(s)
Haimovici, Aladin | |
Humbert, Magali | |
Federzoni, Elena A | |
Shan-Krauer, Deborah | |
Brunner, Thomas | |
Frese, Steffen | |
Torbett, Bruce E |
Additional Credits
Journal
Cell death and differentiation
Publisher
Nature Publishing Group
ISSN
1350-9047
Access(Rights)
restricted