Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB

•IKK/NF-κB signaling sustains the MLL leukemia stem cell program•RELA occupies the HOXA9 and MEIS1 promoters to regulate their expression•IKK/NF-κB is required for MLL protein retention on crucial target genes•Epigenetic regulation by MLL oncoproteins depends on NF-κB

SummaryMLL fusion proteins in leukemia induce aberrant transcriptional elongation and associated chromatin perturbations; however, the upstream signaling pathways and activators that recruit or retain MLL oncoproteins at initiated promoters are unknown. Through functional and comparative genomic studies, we identified an essential role for NF-κB signaling in MLL leukemia. Suppression of NF-κB led to robust antileukemia effects that phenocopied loss of functional MLL oncoprotein or associated epigenetic cofactors. The NF-κB subunit RELA occupies promoter regions of crucial MLL target genes and sustains the MLL-dependent leukemia stem cell program. IKK/NF-κB signaling is required for wild-type and fusion MLL protein retention and maintenance of associated histone modifications, providing a molecular rationale for enhanced efficacy in therapeutic targeting of this pathway in MLL leukemias.