title: Treatment with 5-azacytidine accelerates acute promyelocytic leukemia leukemogenesis in a transgenic mouse model.
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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
authors.forename: Lu Fan
authors.initials: LF
authors.lastname: Cai
authors.forename: Samia M
authors.initials: SM
authors.lastname: Majid
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Yung
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi