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.