title: Inhibition of leukemic cells by valproic acid, an HDAC inhibitor, in xenograft tumors.
abstract: The chimeric fusion protein, AML1-ETO, generated by translocation of t(8;21), abnormally recruits histone deacetylase (HDAC) to the promoters of AML1 target genes, resulting in transcriptional repression of the target genes and development of t(8;21) acute myeloid leukemia. Abnormal expression of cyclin-dependent kinase inhibitors, especially p21, is considered a possible mechanism of the arrested maturation and differentiation seen in leukemia cells. A new generation of HDAC inhibitors is becoming an increasing focus of attention for their ability to induce differentiation and apoptosis in tumor cells and to block the cell cycle. Our previous research had demonstrated that valproic acid induces G0/G1 arrest of Kasumi-1 cells in t(8;21) acute myeloid leukemia. In this study, we further confirmed that valproic acid inhibits the growth of Kasumi-1 cells in a murine xenograft tumor model, and that this occurs via upregulation of histone acetylation in the p21 promoter region, enhancement of p21 expression, suppression of phosphorylation of retinoblastoma protein, blocking of transcription activated by E2F, and induction of G0/G1 arrest.
authors.affiliation: Hematology Department, Affiliated Hospital of Chengde Medical College, Chengde, Hebei Province, People's Republic of China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.forename: Changlai
authors.initials: C
authors.lastname: Hao
authors.forename: Lihong
authors.initials: L
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Cuimin
authors.initials: C
authors.lastname: Zhu
authors.forename: Xia
authors.initials: X
authors.lastname: Tian
keywords: AML1-ETO; E2F; acute myeloid leukemia; p21; valproic acid