MLL-ENL Inhibits Polycomb Repressive Complex 1 to Achieve Efficient Transformation of Hematopoietic Cells

Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay, and this effect was neutralized by direct association with ENL. Correspondingly, CBX8-binding-defective MLL-ENL could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as a neomorphic activity that may augment Polycomb inhibition and transformation. [Display omitted] •The MLL fusion partner ENL copurifies with Polycomb repressive complex 1•A direct interaction of ENL with CBX8 blocks Polycomb repressive activity•Inhibition of Polycomb is necessary for MLL-ENL-induced transformation•Dimerization of MLL-ENL combines Polycomb inhibition with stimulation of elongation Transcription depends on active RNA PolII but also needs a permissive chromatin environment. Slany and colleagues now provide evidence that stimulation of transcription elongation by an MLL fusion concomitantly blocks Polycomb-mediated repression, with both functions being necessary for cellular transformation. This uncovers interplay between competing transcriptional control mechanisms and will aid understanding of Polycomb mutant phenotypes encountered in cancer cells.