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, 100 bone marrow samples from patients with acute lymphoblastic leukemia (ALL) were cultured in the presence of TNFα, GM-CSF, c-kit ligand and FLT3 ligand with or without interleukin-3 and –4, and after administration of the HdI valproic acid (VAL), suberoylanilide hydroxamic acid (SAHA), isobutyramid or trichostatin A. Twenty-six of these ALL samples were positive for the t(12;21) translocation encoding the fusion gene TEL/AML1. SAHA increased CD83 expression of TEL/AML1- positive blasts in conditions without interleukins (36±6.5% versus 26.3±7.1%, p< 0.05), while SAHA and VAL increased the number of CD86(+)80(−) cells in the presence of interleukins (12.5±2.8 ×10⁴ versus 6.3±1.1 ×10⁴ cells). VAL and isobutyramid supported the allostimulatory capacities of TEL/AML1-positive leukemic DC (48.5±6.4 ×10³cpm and 50.3±7.1 ×10³cpm) and reduced those of TEL/AML1-negative DC (41.8±6.8 ×10³ cpm versus 52.8±11.2 ×10³cpm, p= 0.05). Cytotoxic T-cells sensitized with leukemic DC produced more INFγ and TNFα upon presentation of the TEL/AML1 peptide. They also induced the cytotoxic lysis of non-differentiated blasts, which was enhanced when TEL/AML1-positive DC had developed after addition of VAL or SAHA. In conclusion, the use of HdI in the differentiation of leukemic DC from patients with TEL/AML1-positive ALL is recommended.