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.
J.N. was supported by the Damon Runyon Cancer Research Foundation. I.A. was supported by the US National Institutes of Health (RO1CA133379, RO1CA105129, R21CA141399, RO1CA149655 and RO1GM088847), The Leukemia & Lymphoma Society, The V Foundation, the American Cancer Society (RSG0806801) and the Dana Foundation. The Aifantis laboratory is also supported by a Feinberg Lymphoma Pilot grant. This study was also supported by the Fund for Scientific Research of Flanders (P.V.V. and K.D.K.); the US National Library of Medicine (1R01LM010140-01 to R.R.); the Eastern Cooperative Oncology Group tumor bank; a Northeast Biodefense Center American Recovery and Reinvestment Act award (U54-AI057158 to R.R.); the US National Institutes of Health (R01CA120196 and R01CA155743 to A.F.); the Stand Up To Cancer Innovative Research Award (A.F.), the Chemotherapy Foundation (I.A. and A.F.); the Rally Across America Foundation (A.F.) and the Swim Across America Foundation (A.F.). P.V.V. is an American Society of Hematology Scholar, and I.A. and A.F. are Leukemia & Lymphoma Society Scholars. M.D. is supported by grants from Spanish Ministerio de Ciencia e Innovación (BFU2009-09074 and MECCONSOLIDER CSD2007-00023), Generalitat Valenciana (PROMETEO2006/134) and an EU Research Grant (UE-HEALH-F2-2008-201666). F.P. is supported by the Institut du Cancer, the Association Laurette Fugain, the Ligue National Contre le Cancer and also by INSERM, CEA and StemPole. S.P. is supported by a fellowship by the Institut du Cancer. I.A. is a Howard Hughes Medical Institute Early Career Scientist.