Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells.
Histone deacetylase inhibitors (HDACIs) have been used to focus on the effects of inducing gene expression through the acetylation of histones which results in chromatin remodeling. The study explored whether HDACIs could induce the expression of costimulatory/adhesion molecules on acute myeloid leukemia (AML) cells, thereby effectively inducing tumor immunity. The expression of CD80, CD86, human leukocyte antigen (HLA)-DR, HLA-ABC, and intracellular adhesion molecule-1 (ICAM-1) was tested in human AML cell lines after the addition of HDACI, sodium butyrate (SB). Generally, increased expression of CD86 was observed by SB treatment in a majority of cell lines, and ICAM-1 was expressed in fewer cell lines. Essentially the same results were obtained using other HDACIs such as FR901228, trichostatin A, and trapoxin A. Quantitation of transcripts of CD86 accompanied with RNA synthesis inhibition assay and nuclear run-on assay revealed that SB up-regulates the CD86 expression transcriptionally. Furthermore, chromatin immunoprecipitation experiments showed that HDACI treatment caused remarkable acetylation on histone H3 and H4 at CD86 promoter chromatin in vivo. In 30 clinical AML samples, CD86 expression was significantly increased (P <.001) by SB treatment, and the expression of HLA-DR and ICAM-1 was moderately increased (P <.05) by SB treatment. Finally, the allogeneic mixed leukocyte reaction (allo-MLR) against HL60 cells pretreated with SB was enhanced 4-fold compared with allo-MLR obtained with non-treated HL60 cells. These results suggest that the immunotherapeutic use of HDACIs may become a novel tool for treatment of AML. (Blood. 2000;96:3847-3856)
Maeda
T
T
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan.
Towatari
M
M
Kosugi
H
H
Saito
H
H
D000107:Acetylation / Q000187:drug effects; D000208:Acute Disease; D015703:Antigens, CD / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051940:B7-2 Antigen; D020148:Butyric Acid / Q000276:immunology / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation; D002843:Chromatin; D004791:Enzyme Inhibitors / Q000276:immunology / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; D015815:Cell Adhesion Molecules; D002843:Chromatin; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D020148:Butyric Acid; D018799:Intercellular Adhesion Molecule-1; D014212:Tretinoin; D007371:Interferon-gamma