Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB

Hsu Ping Kuo, Zhong Wang, Dung Fang Lee, Masayuki Iwasaki, Jesus Duque-Afonso, Stephen H.K. Wong, Chiou Hong Lin, Maria E. Figueroa, Jie Su, Ihor R. Lemischka, Michael L. Cleary

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)423-437
Number of pages15
JournalCancer Cell
Volume24
Issue number4
DOIs
StatePublished - Oct 14 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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