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

Pier Paolo Scaglioni, Lu Fan Cai, Samia M. Majid, Thomas M. Yung, Nicholas D. Socci, Scott C. Kogan, Levy Kopelovich, Pier Paolo Pandolfi

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)160-165
Number of pages6
JournalGenes and Cancer
Volume2
Issue number2
DOIs
StatePublished - Jul 12 2011

Keywords

  • 5-azacytidine
  • Apl
  • Atra
  • Chemoprevention
  • Western diet

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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