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 journalArticle

1 Citation (Scopus)

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 - 2011

Fingerprint

Azacitidine
Acute Promyelocytic Leukemia
Transgenic Mice
Tretinoin
Therapeutics
Leukemia
Retinoic Acid Receptors
Oncogene Proteins
Methyltransferases
Choline
Hispanic Americans
Folic Acid
Chromosome Aberrations
Fats
Pharmacology
Apoptosis
Diet
DNA

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Scaglioni, P. P., Cai, L. F., Majid, S. M., Yung, T. M., Socci, N. D., Kogan, S. C., ... Pandolfi, P. P. (2011). Treatment with 5-azacytidine accelerates acute promyelocytic Leukemia leukemogenesis in a transgenic mouse model. Genes and Cancer, 2(2), 160-165. https://doi.org/10.1177/1947601911410300

Treatment with 5-azacytidine accelerates acute promyelocytic Leukemia leukemogenesis in a transgenic mouse model. / Scaglioni, Pier Paolo; Cai, Lu Fan; Majid, Samia M.; Yung, Thomas M.; Socci, Nicholas D.; Kogan, Scott C.; Kopelovich, Levy; Pandolfi, Pier Paolo.

In: Genes and Cancer, Vol. 2, No. 2, 2011, p. 160-165.

Research output: Contribution to journalArticle

Scaglioni, PP, Cai, LF, Majid, SM, Yung, TM, Socci, ND, Kogan, SC, Kopelovich, L & Pandolfi, PP 2011, 'Treatment with 5-azacytidine accelerates acute promyelocytic Leukemia leukemogenesis in a transgenic mouse model', Genes and Cancer, vol. 2, no. 2, pp. 160-165. https://doi.org/10.1177/1947601911410300
Scaglioni, Pier Paolo ; Cai, Lu Fan ; Majid, Samia M. ; Yung, Thomas M. ; Socci, Nicholas D. ; Kogan, Scott C. ; Kopelovich, Levy ; Pandolfi, Pier Paolo. / Treatment with 5-azacytidine accelerates acute promyelocytic Leukemia leukemogenesis in a transgenic mouse model. In: Genes and Cancer. 2011 ; Vol. 2, No. 2. pp. 160-165.
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