Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins Journal Article
| Authors: | Moldenhauer, A.; Frank, R. C.; Pinilla-Ibarz, J.; Holland, G.; Boccuni, P.; Scheinberg, D. A.; Salama, A.; Seeger, K.; Moore, M. A. S.; Nimer, S. D. |
| Article 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-Bke leukemia-AML1. These fusion proteins are implicated in the pathogenesis of the lenkende 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 α, 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. |
| Keywords: | controlled study; leukemia; human cell; dna-binding proteins; proto-oncogene proteins; pathogenesis; stem cell factor; enzyme inhibition; dendritic cell; cd40 ligand; granulocyte macrophage colony stimulating factor; cytogenetics; cell differentiation; cytotoxicity; cell line, tumor; transcription factors; cytokine; lymphocyte activation; cytokines; dendritic cells; lymphocyte culture test, mixed; immune response; hybrid protein; tumor necrosis factor alpha; enzyme inhibitors; membrane glycoproteins; hla dr antigen; hla-dr antigens; vaccination; t-lymphocytes, cytotoxic; oncogene proteins, fusion; hydroxamic acids; chromosome translocation; antigens, cd; histone deacetylases; cd83 antigen; histone deacetylase; core binding factor alpha 2 subunit; leukemia cell line; trichostatin a; immunoglobulins; transcription factor runx1; translocation; humans; human; priority journal; article |
| Journal Title: | Journal of Leukocyte Biology |
| Volume: | 76 |
| Issue: | 3 |
| ISSN: | 0741-5400 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 2004-09-01 |
| Start Page: | 623 |
| End Page: | 633 |
| Language: | English |
| DOI: | 10.1189/jlb.1103581 |
| PROVIDER: | scopus |
| PUBMED: | 15197237 |
| DOI/URL: | |
| Notes: | J. Leukocyte Biol. -- Cited By (since 1996):18 -- Export Date: 16 June 2014 -- CODEN: JLBIE -- Source: Scopus |
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