p53-independent epigenetic repression of the p21(WAF1) gene in T-cell acute lymphoblastic leukemia

• Published in: The Journal of biological chemistry 2011-10, Vol.286 (43), p.37639
• Main Authors: Davies, Carwyn, Hogarth, Linda A, Dietrich, Philipp A, Bachmann, Petra S, Mackenzie, Karen L, Hall, Andrew G, Lock, Richard B
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Adolescent; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Child; Child, Preschool; CpG Islands - genetics; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA Damage - drug effects; DNA Damage - genetics; DNA Methylation - drug effects; DNA Methylation - genetics; Epigenesis, Genetic; Etoposide - pharmacology; Female; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Histone Deacetylase Inhibitors - pharmacology; Histones - genetics; Histones - metabolism; Humans; Hydroxamic Acids - pharmacology; Jurkat Cells; Male; Mice; Mice, SCID; Neoplasm Transplantation; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Promoter Regions, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; Transplantation, Heterologous; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Vorinostat
• ISSN: 1083-351X
• DOI: 10.1074/jbc.M111.272336

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).