Treatment with 5-azacytidine accelerates acute promyelocytic Leukemia leukemogenesis in a transgenic mouse model Journal Article
| Authors: | Scaglioni, P. P.; Cai, L. F.; Majid, S. M.; Yung, T. M.; Socci, N. D.; Kogan, S. C.; Kopelovich, L.; Pandolfi, P. P. |
| Article 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. © The Author(s) 2011. |
| Keywords: | cancer survival; controlled study; nonhuman; disease free survival; mouse; animal tissue; cancer prevention; animal experiment; animal model; mus musculus; leukemogenesis; promyelocytic leukemia; choline; folic acid; retinoic acid; azacitidine; promyelocytic leukemia protein; retinoic acid receptor alpha; chemoprevention; lipid diet; 5-azacytidine; apl; atra; western diet |
| Journal Title: | Genes and Cancer |
| Volume: | 2 |
| Issue: | 2 |
| ISSN: | 1947-6019 |
| Publisher: | Sage Publications |
| Date Published: | 2011-02-01 |
| Start Page: | 160 |
| End Page: | 165 |
| Language: | English |
| DOI: | 10.1177/1947601911410300 |
| PROVIDER: | scopus |
| PMCID: | PMC3111249 |
| PUBMED: | 21779489 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 17 August 2011" - "Source: Scopus" |
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