title: The tumor suppressor gene DAPK2 is induced by the myeloid transcription factors PU.1 and C/EBPα during granulocytic differentiation but repressed by PML-RARα in APL.
abstract: DAPK2 is a proapoptotic protein that is mostly expressed in the hematopoietic tissue. A detailed DAPK2 expression analysis in two large AML patient cohorts revealed particularly low DAPK2 mRNA levels in APL. DAPK2 levels were restored in APL patients undergoing ATRA therapy. PML-RARA is the predominant lesion in APL causing transcriptional repression of genes important for neutrophil differentiation. We found binding of PML-RARA and PU.1, a myeloid master regulator, to RARA and PU.1 binding sites in the DAPK2 promoter. Ectopic expression of PML-RARA in non-APL, as well as knocking down PU.1 in APL cells, resulted in a significant reduction of DAPK2 expression. Restoring DAPK2 expression in PU.1 knockdown APL cells partially rescued neutrophil differentiation, thereby identifying DAPK2 as a relevant PU.1 downstream effector. Moreover, low DAPK2 expression is also associated with C/EBPα-mutated AML patients, and we found C/EBPα-dependent regulation of DAPK2 during APL differentiation. In conclusion, we identified first inhibitory mechanisms responsible for the low DAPK2 expression in particular AML subtypes, and the regulation of DAPK2 by two myeloid transcription factors underlines its importance in neutrophil development.
authors.affiliation: 1.Division of Experimental Pathology, TP2, University of Bern, Murtenstrasse 31, P.O. Box 62, CH-3010 Bern, Switzerland. mario.tschan@pathology.unibe.ch.
authors.forename: Magali
authors.initials: M
authors.lastname: Humbert
authors.forename: Elena A
authors.initials: EA
authors.lastname: Federzoni
authors.forename: Adrian
authors.initials: A
authors.lastname: Britschgi
authors.forename: Anna M
authors.initials: AM
authors.lastname: Schläfli
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Thomas
authors.initials: T
authors.lastname: Kaufmann
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
authors.forename: Hans-Uwe
authors.initials: HU
authors.lastname: Simon
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fey
authors.forename: Mario P
authors.initials: MP
authors.lastname: Tschan
mesh_terms: D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D064550:Death-Associated Protein Kinases; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
keywords: APL; DRP-1; acute myeloid leukemia; neutrophil
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