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

Haimovici, Aladin; Humbert, Magali; Federzoni, Elena A; Shan-Krauer, Deborah; Brunner, Thomas; Frese, Steffen; Kaufmann, Thomas; Torbett, Bruce E; Tschan, Mario (2017). PU.1 supports TRAIL-induced cell death by inhibiting NF-κB-mediated cell survival and inducing DR5 expression. Cell death and differentiation, 24(5), pp. 866-877. Nature Publishing Group 10.1038/cdd.2017.40

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

UniBE Contributor:

Kaufmann, Thomas and Tschan, Mario

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1350-9047

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Jana Berger

Date Deposited:

17 Aug 2017 16:43

Last Modified:

09 Sep 2017 06:22

Publisher DOI:

10.1038/cdd.2017.40

PubMed ID:

28362429

BORIS DOI:

10.7892/boris.99554

URI:

https://boris.unibe.ch/id/eprint/99554

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