| Title: |
Treatment with 5-azacytidine accelerates acute promyelocytic leukemia leukemogenesis in a transgenic mouse model. |
| Authors: |
Scaglioni PP; Cai LF; Majid SM; Yung TM; Socci ND; Kogan SC; Kopelovich L; PANDOLFI DE RINALDIS, Pier Paolo |
| Contributors: |
Scaglioni PP; Cai LF; Majid SM; Yung TM; Socci ND; Kogan SC; Kopelovich L; Pandolfi PP |
| Publication Year: |
2011 |
| Collection: |
Università degli studi di Torino: AperTo (Archivio Istituzionale ad Accesso Aperto) |
| Subject Terms: |
APL; 5-azacytidine; ATRA; Western diet; chemoprevention |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/21779489; volume:2; firstpage:160; lastpage:165; numberofpages:5; journal:GENES & CANCER; http://hdl.handle.net/2318/88893; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-79960037264; http://dx.doi.org/10.1177/1947601911410300; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111249/pdf/10.1177_1947601911410300.pdf |
| DOI: |
10.1177/1947601911410300 |
| Availability: |
http://hdl.handle.net/2318/88893; https://doi.org/10.1177/1947601911410300; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111249/pdf/10.1177_1947601911410300.pdf |
| Accession Number: |
edsbas.1C813162 |
| Database: |
BASE |