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Faber J, Gregory RI, and Armstrong SA,
"Linking miRNA Regulation to BCR-ABL Expression: The Next Dimension ",
Cancer Cell, vol. 13, no. 6, pp. 467-469 (June 10,  2008).
 

"Linking miRNA Regulation to BCR-ABL Expression: The Next Dimension".

Jörg Faber ¹, Richard I. Gregory ¹, and Scott A. Armstrong ¹,

¹ Division of Hematology/Oncology, Children's Hospital Boston, Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA

e-mail: scott.armstrong@childrens.harvard.edu

The introduction of tyrosine kinase inhibitors in the treatment of BCR-ABL1-rearranged malignancies has revolutionized therapy, but the prognosis for acute leukemias remains suboptimal. In this issue of Cancer Cell, Bueno et al. (2008) add a new dimension to the regulation of ABL1 expression. The authors demonstrate that ABL1 is a direct target of miR-203, miR-203 is silenced by genetic and epigenetic mechanisms in hematopoietic malignancies expressing either ABL1 or BCR-ABL1, and restoration of miR-203 expression reduces ABL1 and BCR-ABL1 levels and inhibits cell proliferation. These findings may have broad implications for mechanisms underlying malignant transformation in hematopoietic and other malignancies.

Figure 1. Model of ABL1 and BCR-ABL1 Regulation by miR-203.

miR-203 is silenced by both genetic and epigenetic mechanisms in lymphomas expressing high levels of ABL1 and in BCR-ABL1-rearranged leukemias. The loss of MiR-203 leads to elevated expression of its direct targets ABL1 and BCR-ABL1, which enhances cell proliferation.

Cancer Cell, Volume 13, Issue 6, 10 June 2008, Pages 496-506.

"Genetic and Epigenetic Silencing of MicroRNA-203 Enhances ABL1 and BCR-ABL1 Oncogene Expression".

María J. Bueno ^{1, 2}, Ignacio Pérez de Castro ¹, Marta Gómez de Cedrón ¹, Javier Santos ², George A. Calin ³, Juan C. Cigudosa ⁴, Carlo M. Croce ⁵, José Fernández-Piqueras ², Marcos Malumbres ¹

¹ Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain
² Centro de Biología Molecular Severo Ochoa CSIC-Universidad Autónoma de Madrid (UAM) and Department de Biología, UAM, 28049 Madrid, Spain
³ University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
⁴ Molecular Cytogenetics Group, CNIO, E-28029 Madrid, Spain
⁵ The Ohio State University, Comprehensive Cancer Center, Columbus, OH 43210, USA

e-mail:  malumbres@cnio.es

Abstract:

The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelphia chromosome). Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1-dependent manner. Thus, miR-203 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in specific hematopoietic malignancies.

Figure 1. Model of ABL1 and BCR-ABL1 Regulation by miR-203.

miR-203 is silenced by both genetic and epigenetic mechanisms in lymphomas expressing high levels of ABL1 and in BCR-ABL1-rearranged leukemias. The loss of MiR-203 leads to elevated expression of its direct targets ABL1 and BCR-ABL1, which enhances cell proliferation.

Outline of Article:

Significance
Introduction
Results
A Chromosomal Region Enriched in MicroRNAs Is Frequently Lost in Irradiated T Cell Lymphomas
Genetic and Epigenetic Alteration of Mouse and Human miR-203
miR-203 Directly Regulates ABL1 Expression
Specific Methylation of miR-203 in Philadelphia-Positive Human Leukemias
Modulation of ABL1 and BCR-ABL1 Expression by miR-203 and Epigenetic Drugs
Discussion
Experimental Procedures
Mouse Colony and Induction of Tumors
Comparative Genome Hybridization
LOH Analysis
MicroRNA and cDNA Expression Analysis
DNA Methylation Analysis
DNA Transfection and Retroviral Infection
Protein Analysis and Luciferase Assays
Acknowledgements
Accession Numbers
Supplemental Data
References

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"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA". (PowerPoint Presentation).