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

   


Authors: 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.; Keersmaecker, K. D.; Patel, J.; Huynh, T.; Utro, F.; Poglio, S.; Samon, J. B.; Paietta, E.; Racevskis, J.; Rowe, J. M.; Rabadan, R.; Levine, R. L.; Brown, S.; Pflumio, F.; Dominguez, M.; Ferrando, A.; Aifantis, I.
Article Title: Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia
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) 4 by 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. © 2012 Nature America, Inc. All rights reserved.
Keywords: signal transduction; controlled study; protein expression; carrier protein; unclassified drug; dna binding protein; gene translocation; human cell; gene deletion; genetics; dna-binding proteins; nonhuman; mouse; animal; metabolism; animals; mice; gene expression; gene expression profiling; amino acid substitution; nuclear protein; protein protein interaction; animal experiment; animal model; transcription factor; transcription factor hes 1; receptor, notch1; cell line, tumor; acute lymphoblastic leukemia; physiology; transcription factors; nuclear proteins; gene expression regulation; gene expression regulation, neoplastic; transcription regulation; oligonucleotide array sequence analysis; cell transformation; epigenesis, genetic; histone-lysine n-methyltransferase; nucleotide sequence; leukemogenesis; carrier proteins; tumor cell line; binding site; gene inactivation; dna microarray; gene silencing; repressor protein; repressor proteins; loss of function mutation; genetic epigenesis; thymocyte; receptor binding; polycomb group protein; notch1 receptor; precursor t-cell lymphoblastic leukemia-lymphoma; histone lysine methyltransferase; transcription factor ezh2; ezh2 protein, mouse; cross linking; histone methylation; ezh2 protein, human; notch1 protein, human; polycomb repressive complex 2; transcription factor suz12; suz12 protein, human; suz12 protein, mouse
Journal Title: Nature Medicine
Volume: 18
Issue: 2
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2012-02-06
Start Page: 296
End Page: 301
Language: English
DOI: 10.1038/nm.2651
PROVIDER: scopus
PMCID: PMC3274628
PUBMED: 22237151
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-84856747744&partnerID=40&md5=47afea5a45e0a40d056512421fbee19a
Notes: --- - "Export Date: 1 March 2012" - "CODEN: NAMEF" - "Source: Scopus"
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MSK Authors
  1. Ross Levine
    778 Levine
  2. Jay Prakash Patel
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