Histone deacetylase inhibitors up-regulate costimulatory/adhesion molecules in acute myeloid leukemia cells

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Histone deacetylase Inhibitors (HDACIs) are thought to inhibit the enzymatic activity of histone deacetylase, and to enhance the transcriptional activity of several genes. Modulation of immune responses through acetylation and deacetylation is poorly understood. We hypothesized that acetylation and deacetylation are among the major mechanisms in the regulation of costimulatory/adhesion molecules.We explored whether HDACIs could induce the expression of costimulatory/adhesion molecules on acute myeloid leukemia (AML) cells, thereby effectively inducing tumor immunity. We first tested the expression of CD80, CD86, HLA-DR, HLA-ABC and ICAM-1 after the addition of HDACI, sodium butyrate (SB), in human AML cell lines. Generally, increased expression of CD86 was observed by SB treatment in a majority of cell lines, and that of ICAM-1 was expressed in a fewer cell lines examined. Essentially the same results were obtained by the other HDACIs, FR901228, trichostatin A, and trapoxin A. Quantitation of transcripts of CD86 in accompany with RNA synthesis inhibition assay and nuclear runon assay revealed that SB up-regulates the CD86 expression transcriptionally. Furthermore, chromatin immunoprecipitation (ChlP) experiments showed HDACI treatment caused remarkable acetylation on histone H3 and H4 at CD86 promoter chromatin in vivo. In thirty clinical AML samples, CD86 expression was significantly increased (P<0.001) and that of HLA-DR and ICAM-1 was moderately increased (P<0.05) by SB treatment. Finally, the allogeneic mixed leukocyte reaction (allo-MLR) against HL60 cells pretreated with SB was enhanced 4-fold over that obtained with non-treated HL60 cells. These results suggest that the immunotherapeutic use of HDACIs may become a novel tool for treatment of AML.

元の言語英語
ジャーナルBlood
96
発行部数11 PART I
出版物ステータス出版済み - 12 1 2000
外部発表Yes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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