title: PU.1 supports TRAIL-induced cell death by inhibiting NF-κB-mediated cell survival and inducing DR5 expression.
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.
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, Bern, Switzerland.
authors.forename: Aladin
authors.initials: A
authors.lastname: Haimovici
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Magali
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Federzoni
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Shan-Krauer
authors.affiliation: Chair of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brunner
authors.affiliation: Department of Thoracic Surgery, ELK Berlin Chest Hospital, Berlin, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Frese
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland.
authors.forename: Thomas
authors.identifier: 0000-0001-9906-874X
authors.initials: T
authors.lastname: Kaufmann
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
authors.affiliation: Division of Experimental Pathology, Institute of Pathology, University of Bern, Bern, Switzerland.|Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, Bern, Switzerland.
authors.forename: Mario P
authors.identifier: 0000-0001-5897-3647
authors.initials: MP
authors.lastname: Tschan
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000099232:Proto-Oncogene Protein Spi-1; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human