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p53-independent Epigenetic Repression of the p21^WAF1 Gene in T-cell Acute Lymphoblastic Leukemia

Lookup NU author(s): Dr Linda Hogarth, Dr Andrew Hall

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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).

Publication metadata

Author(s): Davies C, Hogarth LA, Dietrich PA, Bachmann PS, Mackenzie KL, Hall AG, Lock RB

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2011

Volume: 286

Issue: 43

Pages: 37639-37650

Print publication date: 28/10/2011

ISSN (print): 0021-9258

ISSN (electronic): 1067-8816

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M111.272336

DOI: 10.1074/jbc.M111.272336

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