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

• Published in: Genes & cancer 2011-02, Vol.2 (2), p.160-165
• Main Authors: Scaglioni, Pier Paolo, Cai, Lu Fan, Majid, Samia M, Yung, Thomas M, Socci, Nicholas D, Kogan, Scott C, Kopelovich, Levy, Pandolfi, Pier Paolo
• Format: Article
• Language: English
• Subjects: Short Reports
• ISSN: 1947-6019; 1947-6027; 1947-6027
• DOI: 10.1177/1947601911410300

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.