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 signaling. 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), 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) 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.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ntziachristos
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.forename: Jelena
authors.initials: J
authors.lastname: Nedjic
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.forename: Maria Sol
authors.initials: MS
authors.lastname: Flaherty
authors.forename: Dolors
authors.initials: D
authors.lastname: Ferres-Marco
authors.forename: Vanina
authors.initials: V
authors.lastname: da Ros
authors.forename: Zuojian
authors.initials: Z
authors.lastname: Tang
authors.forename: Jasmin
authors.initials: J
authors.lastname: Siegle
authors.forename: Patrik
authors.initials: P
authors.lastname: Asp
authors.forename: Michael
authors.initials: M
authors.lastname: Hadler
authors.forename: Isaura
authors.initials: I
authors.lastname: Rigo
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Jay
authors.initials: J
authors.lastname: Patel
authors.forename: Tien
authors.initials: T
authors.lastname: Huynh
authors.forename: Filippo
authors.initials: F
authors.lastname: Utro
authors.forename: Sandrine
authors.initials: S
authors.lastname: Poglio
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Samon
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Stuart
authors.initials: S
authors.lastname: Brown
authors.forename: Francoise
authors.initials: F
authors.lastname: Pflumio
authors.forename: Maria
authors.initials: M
authors.lastname: Dominguez
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D051881:Receptor, Notch1; D012097:Repressor Proteins; C430461:SUZ12 protein, human; C494163:Suz12 protein, mouse; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2