title: Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins.
abstract: Recurrent cytogenetic abnormalities in leukemic blasts make these an attractive source for dendritic cells (DC) to induce a leukemia-specific immune response. In this study, three leukemic cell lines were investigated: Kasumi-1 and SKNO-1 (two acute myeloid leukemia (AML) cell lines carrying the (8;21)-chromosomal translocation, resulting in the expression of the leukemia-specific fusion protein AML1-eight-twenty-one) and REH, an acute lymphoblastic leukemia cell line with the (12;21)-chromosomal translocation and expression of translocation ETS-like leukemia-AML1. These fusion proteins are implicated in the pathogenesis of the leukemic state by recruiting corepressors and histone deacetylases (HDAC), which interfere with normal cell differentiation. In vitro generation of DC was achieved using a cytokine cocktail containing tumor necrosis factor alpha, granulocyte macrophage-colony stimulating factor, c-kit ligand, and soluble CD40 ligand; yet, addition of the HDAC inhibitor (Hdi) trichostatin A enhanced DC differentiation with retention of the fusion transcripts. These leukemic DC showed high-level CD83 and human leukocyte antigen (HLA)-DR expression and had a high allostimulatory potential. Only DC generated from these cell lines after Hdi induced blast-specific cytotoxic T cell responses in HLA-A-matched T cells with a cytotoxicity of 42% in parental Kasumi-1 and 83% in parental REH cells, respectively. This model system suggests that the Hdi supports the in vitro differentiation of DC from leukemic blasts with AML1-containing fusion proteins.
authors.affiliation: Institute for Transfusion Medicine and Immunehaematology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. anja.moldenhauer@charite.de
authors.forename: Anja
authors.initials: A
authors.lastname: Moldenhauer
authors.forename: Richard C
authors.initials: RC
authors.lastname: Frank
authors.forename: Javier
authors.initials: J
authors.lastname: Pinilla-Ibarz
authors.forename: Gudrun
authors.initials: G
authors.lastname: Holland
authors.forename: Piernicola
authors.initials: P
authors.lastname: Boccuni
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.forename: Abdulgabar
authors.initials: A
authors.lastname: Salama
authors.forename: Karl
authors.initials: K
authors.lastname: Seeger
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
mesh_terms: D015703:Antigens, CD; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007136:Immunoglobulins / Q000276:immunology; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000276:immunology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006684:HLA-DR Antigens; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000097802:CD83 Antigen; C493728:RUNX1 protein, human; C012589:trichostatin A