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Genes Cancer. 2011 Feb;2(2):160-5. doi: 10.1177/1947601911410300.

Treatment with 5-azacytidine accelerates acute promyelocytic leukemia leukemogenesis in a transgenic mouse model.

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  • 1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Abstract

A key oncogenic force in acute promyelocytic leukemia (APL) is the ability of the promyelocytic leukemia-retinoic acid receptor α (PML-RARA) oncoprotein to recruit transcriptional repressors and DNA methyltransferases at retinoic acid-responsive elements. Pharmacological doses of retinoic acid relieve transcriptional repression inducing terminal differentiation/apoptosis of the leukemic blasts. APL blasts often harbor additional recurrent chromosomal abnormalities, and significantly, APL prevalence is increased in Latino populations. These observations suggest that multiple genetic and environmental/dietary factors are likely implicated in APL. We tested whether dietary or targeted chemopreventive strategies relieving PML-RARA transcriptional repression would be effective in a transgenic mouse model. Surprisingly, we found that 1) treatment with a demethylating agent, 5-azacytidine, results in a striking acceleration of APL; 2) a high fat, low folate/choline-containing diet resulted in a substantial but nonsignificant APL acceleration; and 3) all-trans retinoic acid (ATRA) is ineffective in preventing leukemia and results in ATRA-resistant APL. Our findings have important clinical implications because ATRA is a drug of choice for APL treatment and indicate that global demethylation, whether through dietary manipulations or through the use of a pharmacologic agent such as 5-azacytidine, may have unintended and detrimental consequences in chemopreventive regimens.

KEYWORDS:

5-azacytidine; APL; ATRA; Western diet; chemoprevention

PMID:
21779489
[PubMed]
PMCID:
PMC3111249
Free PMC Article

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