NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML
Emily B. Heikamp et al.
Highlights
Degradation of NUP98-fp halts nascent transcription of key oncogenes within 1 h
NUP98-fp loss results in accumulation of PRC1.1 and repressive histone modifications
PRC1.1 is needed for stable gene repression but not for acute transcriptional changes
PRC1.1 is required for leukemia cell differentiation upon Menin inhibitor treatment
Summary
Control of stem cell-associated genes by Trithorax group (TrxG) and Polycomb group (PcG) proteins is frequently misregulated in cancer. In leukemia, oncogenic fusion proteins hijack the TrxG homolog KMT2A and disrupt PcG activity to maintain pro-leukemogenic gene expression, though the mechanisms by which oncofusion proteins antagonize PcG proteins remain unclear. Here, we define the relationship between NUP98 oncofusion proteins and the non-canonical polycomb repressive complex 1.1 (PRC1.1) in leukemia using Menin-KMT2A inhibitors and targeted degradation of NUP98 fusion proteins. Eviction of the NUP98 fusion-Menin-KMT2A complex from chromatin is not sufficient to silence pro-leukemogenic genes. In the absence of PRC1.1, key oncogenes remain transcriptionally active. Transition to a repressed chromatin state requires the accumulation of PRC1.1 and repressive histone modifications. We show that PRC1.1 loss leads to resistance to small-molecule Menin-KMT2A inhibitorsin vivo. Therefore, a critical function of oncofusion proteins that hijack Menin-KMT2A activity is antagonizing repressive chromatin complexes.
