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

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.

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Figure 1: The PRC2 complex as a tumor suppressor in T-ALL.
Figure 2: Notch1-induced epigenetic changes in an in vivo model of T-ALL.
Figure 3: Characterization of T-ALL epigenetic landscape using ChIP-Seq for H3K9ac, H3K4me3 and H3K27me3.
Figure 4: Notch1 binding mediates loss of H3K27me3 and eviction of PRC2 in T-ALL.

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Acknowledgements

We would like to thank R. Bonasio and D. Reinberg (Howard Hughes Medical Institute and NYU School of Medicine) for critical reading of the manuscript and Ezh2-specific antibody; C. Siebel (Genentech) for technical advice; and P. Ballerini, C. Deswartes, T. Leblanc and A. Baruchel (Services d'Hématologie Pédiatrique, Hôpital Trousseau and Hôpital Robert Debré Saint-Louis, respectively) for providing primary human T-ALL samples. We thank M. Gialitakis, L. Parida and G. Stolovitzky for comments on the manuscript and J. Zavadil, B. Berrin and the NYU Genome Technology Center (supported in part by US National Institutes of Health National Cancer Institute P30 CA016087-30 grant) for expert genomic assistance. The NYU Flow Cytometry facility (supported in part by US National Institutes of Health National Cancer Institute grant 5 P30CA16087-31) for expert cell sorting. We also thank the NYU Histology Core (5P30CA16087-31) and the Transgenic Mouse Core (NYU Cancer Institute Center Grant (5P30CA16087-31). 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 MEC-CONSOLIDER 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.

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I.A. and P.N. conceived of the studies, directed research, analyzed the results and wrote the manuscript. P.N. performed xenograft experiments, isolated and characterized mouse samples and performed and analyzed the biochemical experiments, helped by T.T. and J.S. A.T. directed research, analyzed data, developed computational methods and wrote the manuscript. J.N. isolated and characterized mouse samples, helped to project design and wrote the manuscript. S.B., Z.T. and T.H. helped with the analysis of the genome-wide data. P.A. helped with the design and execution of the biochemical experiments. F.U. created the resource website. P.V.V., M.H., I.R., J.B.S. and J.P. performed mutation analysis of SUZ12, EZH2 and EED. R.L.L. designed and supervised sequence analysis. P.V.V. performed xenograft experiments. P.V.V. and K.D.K. performed aCGH analysis. R.R. analyzed aCGH data. M.S.F. performed the genetic silencing studies of PRC2. E.P., J.R. and J.M.R. provided samples and correlative clinical data from the Eastern Cooperative Oncology Group. S.P. and F.P. performed and supervised experiments related to NOTCH activation into primary T-ALL samples and provided crucial materials. A.F. designed the studies, directed research and wrote the manuscript. D.F.-M., V.d.R. and M.D. designed and performed the Drosophila tumor experiments.

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Correspondence to Aristotelis Tsirigos or Adolfo Ferrando or Iannis Aifantis.

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Supplementary Figures 1–26, Supplementary Tables 1–12, Supplementary Data and Supplementary Methods (PDF 17158 kb)

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Ntziachristos, P., Tsirigos, A., Vlierberghe, P. et al. Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 18, 298–302 (2012). https://doi.org/10.1038/nm.2651

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