The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the 
COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene 
enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point 
mutations across a range of human tumor types, but precisely how these lesions 
alter MLL3 function and contribute to oncogenesis is unclear. Here we report a 
cancer mutational hotspot in MLL3 within the region encoding its plant 
homeodomain (PHD) repeats and demonstrate that this domain mediates association 
of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. 
Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats 
disrupt the interaction between MLL3 and BAP1 and correlate with poor patient 
survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 
showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known 
as UTX) to gene enhancers. As a result, inhibition of the H3K27 
methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor 
cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns 
and impaired cell proliferation in vivo. This study provides mechanistic insight 
into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that 
restoration of a balanced state of Polycomb-COMPASS activity may have 
therapeutic efficacy in tumors that bear mutations in the genes encoding these 
epigenetic factors.