biostudies-literatureHumbert MSwiss National Science FoundationNHLBI NIH HHSBernese Foundation of Cancer ResearchUrsula-Hecht-Foundation for Leukemia ResearchMarlies-Schwegler FoundationU.S. National Institutes of HealthJoyce Klein Stock GiftWerner and Hedy Berger-Janser Foundation of Cancer ResearchBern University Research Foundation83-93https://www.ebi.ac.uk/biostudies/studies/S-EPMC3868189biostudies-literatureUnknown95(1)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 aJournal of leukocyte biologyThe 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.PMC3868189R01 HL091219129702129955R01HL09121931003A_12995531003A_129702Haferlach TValk PJSchlafli AMFey MFTorbett BETschan MPSimon HUBritschgi ABehre GHumbert MKaufmann TFederzoni EAfalseThe 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.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 a2014-01-01T00:00:00Z2014 Jan2026-04-14T17:12:58.273Z2025-07-28T03:04:00.684ZS-EPMC38681892403821610.1189/jlb.1112608