Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0808469 on January 16, 2009

Published online before print January 16, 2009
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(Journal of Leukocyte Biology. 2009;85:563-573.)
© 2009 by Society for Leukocyte Biology

Histone deacetylase inhibition improves differentiation of dendritic cells from leukemic blasts of patients with TEL/AML1-positive acute lymphoblastic leukemia

Kerstin Schmidt*, Karl Seeger{dagger}, Carmen Scheibenbogen{ddagger}, Roderich Bender*, Majd Abdulla*, Sina Süssmilch*, Abdulgabar Salama* and Anja Moldenhauer*,1

Institutes for
* Transfusion Medicine and
{ddagger} Immunology and
{dagger} Department of Pediatric Oncology, Charité Campus Virchow-Klinikum and Campus Mitte, Charité–Universitätsmedizin Berlin, Germany

1 Correspondence: Institute for Transfusion Medicine, Campus Virchow-Klinikum, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: anja.moldenhauer{at}charite.de

ABSTRACT

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.

Key Words: valproic acid • suberoylanilide hydroxamic acid • cytotoxic T cells • vaccine • cytokines