Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia

Panagiotis Ntziachristos, Aristotelis Tsirigos, Pieter Van Vlierberghe, Jelena Nedjic, Thomas Trimarchi, Maria Sol Flaherty, Dolors Ferres-Marco, Vanina Da Ros, Zuojian Tang, Jasmin Siegle, Patrik Asp, Michael Hadler, Isaura Rigo, Kim De Keersmaecker, Jay Patel, Tien Huynh, Filippo Utro, Sandrine Poglio, Jeremy B. Samon, Elisabeth PaiettaJanis Racevskis, Jacob M. Rowe, Raul Rabadan, Ross L. Levine, Stuart Brown, Francoise Pflumio, Maria Dominguez, Adolfo Ferrando, Iannis Aifantis

Research output: Contribution to journalArticle

312 Scopus citations

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling1. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2)2,3, in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3)4by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

Original languageEnglish (US)
Pages (from-to)296-301
Number of pages6
JournalNature Medicine
Volume18
Issue number2
DOIs
StatePublished - 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ntziachristos, P., Tsirigos, A., Vlierberghe, P. V., Nedjic, J., Trimarchi, T., Flaherty, M. S., Ferres-Marco, D., Da Ros, V., Tang, Z., Siegle, J., Asp, P., Hadler, M., Rigo, I., De Keersmaecker, K., Patel, J., Huynh, T., Utro, F., Poglio, S., Samon, J. B., ... Aifantis, I. (2012). Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nature Medicine, 18(2), 296-301. https://doi.org/10.1038/nm.2651