title: Valproic acid triggers differentiation and apoptosis in AML1/ETO-positive leukemic cells specifically.
abstract: Valproic acid (VPA) has extensive effects on leukemic blasts through its inhibition of histone deacetylases. The main goal of this study was to identify the subgroup of patients who may benefit most from VPA treatment. We examined the significance of t(8;21) chromosomal aberration for VPA treatment response among acute myeloid leukemia (AML) patients by direct comparison of AML1/ETO-negative vs. positive leukemic cell-lines as well as bone marrow blasts from AML patients. In t(8;21) AML, leukemogenesis is supposed to be induced via aberrant recruitment of histone deacetylases. AML cell lines of different genotypes (Kasumi-1, Kasumi-6, MV4;11, K562) and diagnostic bone marrow samples from patients were treated with VPA. VPA induced apoptosis in AML1/ETO-positive and MLL-AF4-positive cells in a dose-dependent manner. Differentiation, as indicated by changes in immunophenotype, was observed only in AML1/ETO-positive cells. VPA increased the expression of AML1 target genes - PU.1, C/EBPa, BPI and IGFBP7 only in AML1/ETO-positive cells. This AML1/ETO-specific effect was confirmed also using patient blasts isolated at the time of diagnosis. AML1/ETO-positive leukemia shows specific mechanism of VPA residing from differentiation followed by apoptosis that is accompanied by an increase in the expression of repressed AML1 target genes. Our data suggest that AML1/ETO-positive patients might derive the greatest benefit from VPA treatment.
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Zapotocky
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Ester
authors.initials: E
authors.lastname: Mejstrikova
authors.affiliation: Institute of Hematology and Blood Transfusion, Charles University, 1st Medical School, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Smetana
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Stary
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, Charles University, 2nd Medical School, Prague, Czech Republic. Electronic address: jan.trka@lfmotol.cuni.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.affiliation: CLIP, Department of Pediatric Hematology and Oncology, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: Julia
authors.initials: J
authors.lastname: Starkova
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014635:Valproic Acid