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Science 295 (5557): 1079-1082

Copyright © 2002 by the American Association for the Advancement of Science

Methyltransferase Recruitment and DNA Hypermethylation of Target Promoters by an Oncogenic Transcription Factor

Luciano Di Croce,1* Veronica A. Raker,1 Massimo Corsaro,1 Francesco Fazi,2 Mirco Fanelli,15 Mario Faretta,1 Francois Fuks,4 Francesco Lo Coco,3 Tony Kouzarides,4 Clara Nervi,2 Saverio Minucci,1 Pier Giuseppe Pelicci16*

DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential. Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. These results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis.

1 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
2 Department of Histology and Medical Embryology,
3 Department of Cellular Biotechnology and Hematology, University of Rome, "La Sapienza," Rome, Italy.
4 Wellcome/CRC Institute and Department of Pathology, Cambridge University, Cambridge, UK.
5 Department of Morphological Science, University of Camerino, Italy.
6 Italian Foundation for Cancer Research (FIRC) Institute for Molecular Oncology, Milan, Italy.
*   To whom correspondence should be addressed. E-mail: ldicroce{at} (L.D.C.); pgpelicci{at} (P.G.P.)

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K. Hochedlinger, R. Blelloch, C. Brennan, Y. Yamada, M. Kim, L. Chin, and R. Jaenisch (2004)
Genes & Dev. 18, 1875-1885
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Parent-of-Origin-Specific Binding of Nuclear Hormone Receptor Complexes in the H19-Igf2 Imprinting Control Region.
P. E. Szabo, G. P. Pfeifer, and J. R. Mann (2004)
Mol. Cell. Biol. 24, 4858-4868
   Abstract »    Full Text »    PDF »
The Fusion Oncoprotein PML-RAR{alpha} Induces Endoplasmic Reticulum (ER)-associated Degradation of N-CoR and ER Stress.
M. M. Khan, T. Nomura, T. Chiba, K. Tanaka, H. Yoshida, K. Mori, and S. Ishii (2004)
J. Biol. Chem. 279, 11814-11824
   Abstract »    Full Text »    PDF »
Impairment of p53 acetylation, stability and function by an oncogenic transcription factor.
A. Insinga, S. Monestiroli, S. Ronzoni, R. Carbone, M. Pearson, G. Pruneri, G. Viale, E. Appella, P. Pelicci, and S. Minucci (2004)
EMBO J. 23, 1144-1154
   Abstract »    Full Text »    PDF »
The Present State of Antineoplaston Research (1).
S. R. Burzynski (2004)
Integr Cancer Ther 3, 47-58
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The Coiled-coil Domain Is the Structural Determinant for Mammalian Homologues of Drosophila Sina-mediated Degradation of Promyelocytic Leukemia Protein and Other Tripartite Motif Proteins by the Proteasome.
M. Fanelli, A. Fantozzi, P. De Luca, S. Caprodossi, S.-i. Matsuzawa, M. A. Lazar, P. G. Pelicci, and S. Minucci (2004)
J. Biol. Chem. 279, 5374-5379
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Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes.
M. T. Voso, A. Scardocci, F. Guidi, G. Zini, A. Di Mario, L. Pagano, S. Hohaus, and G. Leone (2004)
Blood 103, 698-700
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