Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin

Marco Marra and colleagues identify somatic mutations in EZH2 in diffuse large B-cell lymphomas and follicular lymphomas. EZH2 is a histone methyltransferase that participates in trimethylation of H3 Lys27 (H3K27) as part of the PRC2 complex. The mutations alter a single tyrosine residue in the SET...

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Veröffentlicht in:	Nature genetics Jg. 42; H. 2; S. 181 - 185
Hauptverfasser:	Morin, Ryan D, Johnson, Nathalie A, Severson, Tesa M, Mungall, Andrew J, An, Jianghong, Goya, Rodrigo, Paul, Jessica E, Boyle, Merrill, Woolcock, Bruce W, Kuchenbauer, Florian, Yap, Damian, Humphries, R Keith, Griffith, Obi L, Shah, Sohrab, Zhu, Henry, Kimbara, Michelle, Shashkin, Pavel, Charlot, Jean F, Tcherpakov, Marianna, Corbett, Richard, Tam, Angela, Varhol, Richard, Smailus, Duane, Moksa, Michelle, Zhao, Yongjun, Delaney, Allen, Qian, Hong, Birol, Inanc, Schein, Jacqueline, Moore, Richard, Holt, Robert, Horsman, Doug E, Connors, Joseph M, Jones, Steven, Aparicio, Samuel, Hirst, Martin, Gascoyne, Randy D, Marra, Marco A
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.02.2010 Nature Publishing Group
Schlagworte:	631/208/2489/2487/2486 631/250/2502/2170 692/699/67/1990/291 Adult Aged Agriculture Amino Acid Sequence Animal Genetics and Genomics Base Sequence Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Cancer Research Care and treatment Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Crystal structure DNA Mutational Analysis DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics Enhancer of Zeste Homolog 2 Protein Enzymatic activity Exons - genetics Female Fundamental and applied biological sciences. Psychology Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Function Gene mutations Genetic aspects Genome, Human - genetics Germinal Center - metabolism Germinal Center - pathology Health aspects Health services Hematologic and hematopoietic diseases Human Genetics Humans letter Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoma Lymphoma, Follicular - genetics Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - pathology Male Medical research Medical sciences Methyltransferases Middle Aged Molecular and cellular biology Molecular Sequence Data Mutant Proteins - chemistry Mutant Proteins - genetics Mutant Proteins - metabolism Mutation Mutation - genetics Non-Hodgkin's lymphomas Physiological aspects Polycomb Repressive Complex 2 Risk factors Transcription Factors - chemistry Transcription Factors - genetics Tyrosine - genetics Canada United States Somatic mutation Origin Germinative center Lymphoproliferative syndrome Diffuse large B cell lymphoma Malignant hemopathy Non Hodgkin lymphoma Cancer
ISSN:	1061-4036, 1546-1718, 1546-1718
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Zusammenfassung:	Marco Marra and colleagues identify somatic mutations in EZH2 in diffuse large B-cell lymphomas and follicular lymphomas. EZH2 is a histone methyltransferase that participates in trimethylation of H3 Lys27 (H3K27) as part of the PRC2 complex. The mutations alter a single tyrosine residue in the SET domain of EZH2 and reduce the ability of PRC2 to trimethylate H3K27 in vitro . Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells 1 . Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-κB pathway 2 , 3 that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified 4 . Here we report recurrent somatic mutations affecting the polycomb-group oncogene 5 EZH2 , which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A ( UTX ), which encodes the histone H3K27me3 demethylase UTX, in several cancer types 6 , EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro .
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.518