Journal Article

The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding

S. Mulero-Navarro, J.M. Carvajal-Gonzalez, M. Herranz, E. Ballestar, M.F. Fraga, S. Ropero, M. Esteller and P.M. Fernandez-Salguero

in Carcinogenesis

Volume 27, issue 5, pages 1099-1104
Published in print May 2006 | ISSN: 0143-3334
Published online January 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi344
The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding

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The transcription factor aryl hydrocarbon receptor (AhR) has relevant functions in cell proliferation. Interestingly, the AhR can either promote or inhibit proliferation depending on the cell phenotype. Although recent data reveal potential pathways for AhR signaling in cell proliferation, the mechanisms that regulate its activity in tumor cells remain unknown. Here, we have analyzed promoter hypermethylation as a potential mechanism controlling AhR expression in human tumor cells. AhR promoter CpG methylation was sporadic in a panel of 19 tumor cell lines except for the chronic myeloid leukemia (CML) K562 and the acute lymphoblastic leukemia (ALL) REH. When compared with normal lymphocytes, REH had very low constitutive AhR expression that could be attributed to promoter hypermethylation since treatment with the DNA demethylating agent 5-aza-2′-deoxycitidine (AZA) significantly increased AhR mRNA and protein. These results in leukemia-derived cell lines were further confirmed in primary ALL, where 33% of the patients (7/21) had AhR promoter hypermethylation. Chromatin immunoprecipitation (ChIP) showed that methylation impaired binding of the transcription factor Sp1 to the AhR promoter, thus providing a mechanism for AhR downregulation in REH cells. Therefore, promoter hypermethylation represents a novel epigenetic mechanism downregulating AhR activity in hematological malignancies such as ALL.

Keywords: AhR, aryl hydrocarbon (dioxin) receptor; ALL, acute lymphoblastic leukemia; AZA, 5-aza-2′-deoxicitidine; ChIP, chromatin immunoprecipitation; CML, chronic myeloid leukemia; FBS, fetal bovine serum; MSP, methylation-specific PCR; PCR, polymerase chain reaction

Journal Article.  4035 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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