title: p53-independent epigenetic repression of the p21(WAF1) gene in T-cell acute lymphoblastic leukemia.
abstract: The p53 protein is a primary mediator of cellular apoptosis and growth arrest after exposure to DNA-damaging agents. Previous work has shown that the majority of childhood acute lymphoblastic leukemia (ALL) cases express a wild type p53 gene, although the functionality of the p53 pathway has rarely been validated. In the present study, the integrity of the p53 pathway was investigated in a panel of ALL cell lines and xenografts established from direct patient explants in immune-deficient mice. A focused real-time quantitative reverse transcription PCR array of known p53-regulated genes identified p21(WAF1) (CDKN1A) as the highest ranked gene to be differentially expressed between B-cell precursor (BCP)-ALL and T-ALL xenografts following exposure to the DNA-damaging drug etoposide. Lack of p21(WAF1) induction was observed in six of seven T-ALL xenograft lines, as well as primary T-ALL cells following irradiation exposure, despite an otherwise functional p53 response. Repression of p21(WAF1) in T-ALL cells was associated with decreased acetylated H3K9 localized at its promoter compared with BCP-ALL cells, together with increased CpG methylation within the first exon and intron. Although the histone deacetylase inhibitor vorinostat failed to induce p21(WAF1) in T-ALL samples, the combination of vorinostat and the demethylating agent decitabine reactivated expression of the silenced p21(WAF1) gene in the Molt-4 T-ALL cell line. Considering the known anti-apoptotic function of p21(WAF1), our findings have significant implications for the responses of T- versus BCP-ALL cells to chemotherapeutic drugs that induce p21(WAF1).
authors: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors: Carwyn
authors: C
authors: Davies
authors: Linda A
authors: LA
authors: Hogarth
authors: Philipp A
authors: PA
authors: Dietrich
authors: Petra S
authors: PS
authors: Bachmann
authors: Karen L
authors: KL
authors: Mackenzie
authors: Andrew G
authors: AG
authors: Hall
authors: Richard B
authors: RB
authors: Lock
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000077337:Vorinostat
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077337:Vorinostat; D005047:Etoposide