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Molecular and Cellular Biology, February 2006, p. 1288-1296, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1288-1296.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Recruitment of the Histone Methyltransferase SUV39H1 and Its Role in the Oncogenic Properties of the Leukemia-Associated PML-Retinoic Acid Receptor Fusion Protein

Roberta Carbone,1,§ Oronza A. Botrugno,1 Simona Ronzoni,1 Alessandra Insinga,1,{ddagger} Luciano Di Croce,1,¶ Pier Giuseppe Pelicci,1* and Saverio Minucci1,2*

Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy,1 Department of Biomolecular Sciences and Biotechnologies, University of Milan, Via Celoria 26, 20133 Milan, Italy2

Received 21 October 2005/ Accepted 20 November 2005

Leukemia-associated fusion proteins establish aberrant transcriptional programs, which result in the block of hematopoietic differentiation, a prominent feature of the leukemic phenotype. The dissection of the mechanisms of deregulated transcription by leukemia fusion proteins is therefore critical for the design of tailored antileukemic strategies, aimed at reestablishing the differentiation program of leukemic cells. The acute promyelocytic leukemia (APL)-associated fusion protein PML-retinoic acid receptor (RAR) behaves as an aberrant transcriptional repressor, due to its ability to induce chromatin modifications (histone deacetylation and DNA methylation) and silencing of PML-RAR target genes. Here, we indicate that the ultimate result of PML-RAR action is to impose a heterochromatin-like structure on its target genes, thereby establishing a permanent transcriptional silencing. This effect is mediated by the previously described association of PML-RAR with chromatin-modifying enzymes (histone deacetylases and DNA methyltransferases) and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3.

* Corresponding author. Mailing address: Istituto Europeo di Oncologia, Via Ripamonti 435, 20141 Milan, Italy. Phone for Saverio Minucci: 39-02-57489832. Fax: 39-02-57489851. E-mail: saverio.minucci{at}ifom-ieo-campus.it. Phone for Pier Giuseppe Pelicci: 39-02-57489838. Fax: 39-02-57489851. E-mail: piergiuseppe.pelicci{at}ifom-ieo-campus.it.

§ Present address: Congenia s.r.l., Via Adamello 16, 20139 Milan, Italy.

{ddagger} Present address: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.

Present address: ICREA and Centre de Regulació Genòmica (CRG), Passeig Maritim 37-49, E-08003 Barcelona, Spain.

Molecular and Cellular Biology, February 2006, p. 1288-1296, Vol. 26, No. 4
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.4.1288-1296.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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