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 PAIETTA; JANIS RACEVSKIS; JACOB M ROWE; RAUL RABADAN; ROSS L LEVINE; STUART BROWN; FRANCOISE PFLUMIO; MARIA DOMINGUEZ; ADOLFO FERRANDO; IANNIS AIFANTIS

NATURE MEDICINE.

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2012 vol. 18 p. 298 - 301

1078-8956

T cell acute lymphoblastic leukemia (T-ALL) is an immaturehematopoietic malignancy driven mainly by oncogenicactivation of NOTCH1 signaling1. In this study we report thepresence of loss-of-function mutations and deletions of theEZH2 and SUZ12 genes, which encode crucial componentsof the Polycomb repressive complex 2 (PRC2)2,3, in 25% ofT-ALLs. To further study the role of PRC2 in T-ALL, we usedNOTCH1-dependent mouse models of the disease, as wellas human T-ALL samples, and combined locus-specific andglobal analysis of NOTCH1-driven epigenetic changes. Thesestudies demonstrated that activation of NOTCH1 specificallyinduces loss of the repressive mark Lys27 trimethylation ofhistone 3 (H3K27me3)4 by antagonizing the activity of PRC2.These studies suggest a tumor suppressor role for PRC2 inhuman leukemia and suggest a hitherto unrecognized dynamicinterplay between oncogenic NOTCH1 and PRC2 function forthe regulation of gene expression and cell transformation.