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Inactivating mutations of acetyltransferase genes in B-cell lymphoma

Author

Listed:
  • Laura Pasqualucci

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
    Columbia University)

  • David Dominguez-Sola

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University)

  • Annalisa Chiarenza

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University)

  • Giulia Fabbri

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University)

  • Adina Grunn

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University)

  • Vladimir Trifonov

    (Columbia University)

  • Lawryn H. Kasper

    (St Jude Children’s Research Hospital)

  • Stephanie Lerach

    (St Jude Children’s Research Hospital)

  • Hongyan Tang

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University)

  • Jing Ma

    (The Hartwell Center for Bioinformatics and Biotechnology, St Jude Children’s Research Hospital)

  • Davide Rossi

    (Amedeo Avogadro University of Eastern Piedmont)

  • Amy Chadburn

    (Northwestern University, Feinberg School of Medicine)

  • Vundavalli V. Murty

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
    Columbia University)

  • Charles G. Mullighan

    (St Jude Children’s Research Hospital)

  • Gianluca Gaidano

    (Amedeo Avogadro University of Eastern Piedmont)

  • Raul Rabadan

    (Columbia University)

  • Paul K. Brindle

    (St Jude Children’s Research Hospital)

  • Riccardo Dalla-Favera

    (Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University
    Columbia University
    Columbia University)

Abstract

B-cell non-Hodgkin’s lymphoma comprises biologically and clinically distinct diseases the pathogenesis of which is associated with genetic lesions affecting oncogenes and tumour-suppressor genes. We report here that the two most common types—follicular lymphoma and diffuse large B-cell lymphoma—harbour frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signalling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these two genes. These lesions usually affect one allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumour suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-cell non-Hodgkin’s lymphoma, with direct implications for the use of drugs targeting acetylation/deacetylation mechanisms.

Suggested Citation

  • Laura Pasqualucci & David Dominguez-Sola & Annalisa Chiarenza & Giulia Fabbri & Adina Grunn & Vladimir Trifonov & Lawryn H. Kasper & Stephanie Lerach & Hongyan Tang & Jing Ma & Davide Rossi & Amy Chad, 2011. "Inactivating mutations of acetyltransferase genes in B-cell lymphoma," Nature, Nature, vol. 471(7337), pages 189-195, March.
  • Handle: RePEc:nat:nature:v:471:y:2011:i:7337:d:10.1038_nature09730
    DOI: 10.1038/nature09730
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    Cited by:

    1. Guozhong Jiang & Zhizhong Wang & Zhenguo Cheng & Weiwei Wang & Shuangshuang Lu & Zifang Zhang & Chinedu A. Anene & Faraz Khan & Yue Chen & Emma Bailey & Huisha Xu & Yunshu Dong & Peinan Chen & Zhongxi, 2024. "The integrated molecular and histological analysis defines subtypes of esophageal squamous cell carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Longxia Xu & Hongwen Xuan & Wei He & Liang Zhang & Mengying Huang & Kuai Li & Hong Wen & Han Xu & Xiaobing Shi, 2023. "TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Josefine Radke & Naveed Ishaque & Randi Koll & Zuguang Gu & Elisa Schumann & Lina Sieverling & Sebastian Uhrig & Daniel Hübschmann & Umut H. Toprak & Cristina López & Xavier Pastor Hostench & Simone B, 2022. "The genomic and transcriptional landscape of primary central nervous system lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    4. Misuzu Habazaki & Shinsuke Mizumoto & Hidetoshi Kajino & Tomoya Kujirai & Hitoshi Kurumizaka & Shigehiro A. Kawashima & Kenzo Yamatsugu & Motomu Kanai, 2023. "A chemical catalyst enabling histone acylation with endogenous acyl-CoA," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Laura Selicato & Flavia Esposito & Grazia Gargano & Maria Carmela Vegliante & Giuseppina Opinto & Gian Maria Zaccaria & Sabino Ciavarella & Attilio Guarini & Nicoletta Del Buono, 2021. "A New Ensemble Method for Detecting Anomalies in Gene Expression Matrices," Mathematics, MDPI, vol. 9(8), pages 1-26, April.

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