title: AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor.
abstract: Acute myeloid leukemia (AML)-associated chromosomal translocations result in formation of chimeric transcription factors, such as PML/RARalpha, PLZF/RARalpha, and AML-1/ETO, of which the components are involved in regulation of transcription by chromatin modeling through histone acetylation/deacetylation. The leukemic differentiation block is attributed to deregulated transcription caused by these chimeric fusion proteins, which aberrantly recruit histone-deacetylase (HDAC) activity. One essential differentiation pathway blocked by the leukemic fusion proteins is the vitamin (Vit) D(3) signaling. Here we investigated the mechanisms by which the leukemic fusion proteins interfere with VitD(3)-induced differentiation. The VitD(3)-receptor (VDR) is, like the retinoid receptors RAR, retinoid X receptor, and the thyroid hormone receptor (TR), a ligand-inducible transcription factor. In the absence of ligand, the transcriptional activity of TR and RAR is silenced by recruitment of HDAC activity through binding to corepressors. In the presence of ligand, TR and RAR activate transcription by releasing HDAC activity and by recruiting histone-acetyltransferase activity. Here we report that VDR binds corepressors in a ligand-dependent manner and that inhibition of HDAC activity increases VitD(3) sensitivity of HL-60 cells. Nevertheless, the inhibition of HDAC activity is unable to overcome the block of VitD(3)-induced differentiation caused by PLZF/RARalpha expression. Here we demonstrate that the expression of the translocation products PML/RARalpha and PLZF/RARalpha impairs the localization of VDR in the nucleus by binding to VDR. Furthermore, the overexpression of VDR in U937 cells expressing AML-related translocation products completely abolishes the block of VitD(3)-induced differentiation. Taken together these data indicate that the AML-associated translocation products block differentiation not only by interfering with chromatin-modeling but also by sequestering factors involved in the differentiation signaling pathways, such as VDR in the VitD(3)-induced differentiation.
authors.affiliation: Med. Klinik III/Abtl. Hämatologie, Johann Wolfgang Goethe-Universität, 60590 Frankfurt, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Puccetti
authors.forename: Darja
authors.initials: D
authors.lastname: Obradovic
authors.forename: Tim
authors.initials: T
authors.lastname: Beissert
authors.forename: Andrea
authors.initials: A
authors.lastname: Bianchini
authors.forename: Birgit
authors.initials: B
authors.lastname: Washburn
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Chiaradonna
authors.forename: Simone
authors.initials: S
authors.lastname: Boehrer
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Oliver Gerhard
authors.initials: OG
authors.lastname: Ottmann
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Clara
authors.initials: C
authors.lastname: Nervi
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002762:Cholecalciferol / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D000075142:RUNX1 Translocation Partner 1 Protein; D018167:Receptors, Calcitriol / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; C000607071:RARA protein, human; D000075142:RUNX1 Translocation Partner 1 Protein; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D002762:Cholecalciferol; D014212:Tretinoin; D006655:Histone Deacetylases