Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins

Anja Moldenhauer, Richard C. Frank, Javier Pinilla-Ibarz, Gudrun Holland, Piernicola Boccuni, David A. Scheinberg, Abdulgabar Salama, Karl Seeger, Malcolm A.S. Moore, Stephen D. Nimer

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)623-633
Number of pages11
JournalJournal of Leukocyte Biology
Volume76
Issue number3
DOIs
StatePublished - Sep 2004

Keywords

  • Leukemia
  • Translocation
  • Vaccination

ASJC Scopus subject areas

  • Cell Biology

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    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. (2004). Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins. Journal of Leukocyte Biology, 76(3), 623-633. https://doi.org/10.1189/jlb.1103581