<i>EZH2</i> (enhancer of zeste homolog 2) and <i>MLL3</i> (mixed lineage leukemia 3) encode histone-modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies.
Chromatin immunoprecipitation assays demonstrated that EZH2 was highly enriched around the transcription-start-site of p16, together with H3K27 methylation marks in MLL/ENL and Hoxa9/Meis1 transduced cells but not in E2A/HLF transduced cells.
Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb repressive complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12 or Ezh1/Ezh2 led to proliferation arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines.