TY - JOUR
T1 - Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia
AU - Ntziachristos, Panagiotis
AU - Tsirigos, Aristotelis
AU - Vlierberghe, Pieter Van
AU - Nedjic, Jelena
AU - Trimarchi, Thomas
AU - Flaherty, Maria Sol
AU - Ferres-Marco, Dolors
AU - Da Ros, Vanina
AU - Tang, Zuojian
AU - Siegle, Jasmin
AU - Asp, Patrik
AU - Hadler, Michael
AU - Rigo, Isaura
AU - De Keersmaecker, Kim
AU - Patel, Jay
AU - Huynh, Tien
AU - Utro, Filippo
AU - Poglio, Sandrine
AU - Samon, Jeremy B.
AU - Paietta, Elisabeth
AU - Racevskis, Janis
AU - Rowe, Jacob M.
AU - Rabadan, Raul
AU - Levine, Ross L.
AU - Brown, Stuart
AU - Pflumio, Francoise
AU - Dominguez, Maria
AU - Ferrando, Adolfo
AU - Aifantis, Iannis
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
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U2 - 10.1038/nm.2651
DO - 10.1038/nm.2651
M3 - Article
C2 - 22237151
AN - SCOPUS:84856747744
SN - 1078-8956
VL - 18
SP - 296
EP - 301
JO - Nature Medicine
JF - Nature Medicine
IS - 2
ER -
