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Blood, 18 June 2009, Vol. 113, No. 25, pp. 6411-6418.
Prepublished online as a Blood First Edition Paper on February 11, 2009; DOI 10.1182/blood-2008-07-170589.
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Submitted July 23, 2008
Accepted February 8, 2009
MicroRNA -29b induces global DNA hypomethylation and tumor suppressor gene re-expression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1
Ramiro Garzon, Shujun Liu, Muller Fabbri, Zhongfa Liu, Catherine E.A. Heaphy, Elisa Callegari, Sebastian Schwind, Jiuxia Pang, Jianhua Yu, Natarajan Muthusamy, Violaine Havelange, Stefano Volinia, William Blum, Laura J. Rush, Danilo Perrotti, Michael Andreeff, Clara D. Bloomfield, John C. Byrd, Kenneth Chan, Lai-Chu Wu, Carlo M. Croce, and Guido Marcucci*
Department of Medicine, The Ohio State University, Columbus, OH, United States
The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH, United States
College of Pharmacy, The Ohio State University, Columbus, OH, United States
Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, United States
Section of Molecular Hematology and Therapy, Department of Blood and Bone Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
Department of Molecular & Cellular Biochemistry, The Ohio State University, Columbus, OH, United States
* Corresponding author; email: guido.marcucci{at}osumc.edu.
Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia (AML) cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A and 3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and re-expression of p15INK4b and ESR1 via promoter DNA hypomethylation. While down-regulation of DNMT3A and 3B was the result of a direct interaction of miR-29b with the 3' untranslated regions (UTR) of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3'UTR. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in AML and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.
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