MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression 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 WuCarlo M. Croce, Guido Marcucci

Research output: Contribution to journalArticle

595 Scopus citations

Abstract

Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding 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 cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15INK4b and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3′ untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3′ untranslated regions. Further experiments revealed that miR-29b downregulates 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 acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.

Original languageEnglish (US)
Pages (from-to)6411-6418
Number of pages8
JournalBlood
Volume113
Issue number25
DOIs
StatePublished - 2009

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    Garzon, R., Liu, S., Fabbri, M., Liu, Z., Heaphy, C. E. A., Callegari, E., Schwind, S., Pang, J., Yu, J., Muthusamy, N., Havelange, V., Volinia, S., Blum, W., Rush, L. J., Perrotti, D., Andreeff, M., Bloomfield, C. D., Byrd, J. C., Chan, K., ... Marcucci, G. (2009). MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood, 113(25), 6411-6418. https://doi.org/10.1182/blood-2008-07-170589