Epigenetic roles of MLL oncoproteins are dependent on NF-κB

Cancer Cell. 2013 Oct 14;24(4):423-37. doi: 10.1016/j.ccr.2013.08.019. Epub 2013 Sep 19.


MLL 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival
  • Chromatin / metabolism
  • Dose-Response Relationship, Drug
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Leukemic*
  • Genomics
  • Histone-Lysine N-Methyltransferase
  • Humans
  • I-kappa B Kinase / metabolism
  • Leukemia / genetics
  • Leukemia / metabolism*
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Myeloid-Lymphoid Leukemia Protein / physiology*
  • NF-kappa B / metabolism*
  • Prognosis
  • Promoter Regions, Genetic
  • Signal Transduction
  • Time Factors
  • Transcription Factor RelA / metabolism
  • Transcription, Genetic


  • Chromatin
  • KMT2A protein, human
  • NF-kappa B
  • Transcription Factor RelA
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • I-kappa B Kinase

Associated data

  • GEO/GSE46252