Histone deacetylase inhibition improves differentiation of dendritic cells from leukemic blasts of patients with TEL/AML1-positive acute lymphoblastic leukemia.
Histone deacetylase inhibitors (HdI) could potentially improve the differentiation of leukemic dendritic cells (DC). Therefore, bone marrow samples from 100 children with acute lymphoblastic leukemia (ALL) were cultured in the cytokines TNF-alpha, GM-CSF, c-kit ligand, and fetal liver tyrosine kinase 3 ligand, with or without IL-3 and -4 and after administration of HdI valproic acid (VAL), suberoylanilide hydroxamic acid (SAHA), isobutyramid, or trichostatin A. Among the tested samples, 25 were positive for the chromosomal translocation t(12;21), encoding the fusion gene translocation ETS-like leukemia/acute myeloid leukemia 1 (TEL/AML1). SAHA increased CD83 expression of TEL/AML1-positive blasts in conditions without ILs, and SAHA and VAL increased the number of CD86(+)80(-) cells in the presence of ILs. VAL and isobutyramid supported the allostimulatory capacities of TEL/AML1-positive, leukemic DC; VAL and SAHA reduced those of TEL/AML1-negative DC. Cytotoxic T cells sensitized with leukemic DC produced more IFN-gamma and TNF-alpha upon presentation of the TEL/AML1 peptide. They also induced the cytotoxic lysis of nondifferentiated blasts, which was enhanced when TEL/AML1-positive DC had developed after addition of VAL or SAHA. Therefore, the use of HdI in the differentiation of leukemic DC from patients with TEL/AML1-positive ALL is recommended.
Schmidt
Kerstin
K
Institute for Transfusion Medicine, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany.
Seeger
Karl
K
Scheibenbogen
Carmen
C
Bender
Roderich
R
Abdulla
Majd
M
Süssmilch
Sina
S
Salama
Abdulgabar
A
Moldenhauer
Anja
A
D017951:Antigen Presentation; D001752:Blast Crisis / Q000473:pathology; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002648:Child; D050676:Core Binding Factor Alpha 2 Subunit; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D015514:Oncogene Proteins, Fusion; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007371:Interferon-gamma; D015514:Oncogene Proteins, Fusion; D014409:Tumor Necrosis Factor-alpha; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein