Diagenode

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


Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Sol Flaherty M, Ferres-Marco D, da Ros V, Tang Z, Siegle J, Asp P, Hadler M, Rigo I, De Keersmaecker K, Patel J, Huynh T, Utro F, Poglio S, Samon JB, Paietta E, Racevskis J, Rowe JM, R

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.

Tags
Bioruptor
Chromatin Shearing
ChIP-seq

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Published
January, 2012

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