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 Figueroa, Jie Su, Ihor R. Lemischka, Michael L. Cleary

Research output: Contribution to journalArticle

50 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Oncogene Proteins
Epigenomics
Leukemia
Histone Code
Genetic Promoter Regions
Chromatin
Proteins
Stem Cells
Maintenance
Genes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Kuo, H. P., Wang, Z., Lee, D. F., Iwasaki, M., Duque-Afonso, J., Wong, S. H. K., ... Cleary, M. L. (2013). Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB. Cancer Cell, 24(4), 423-437. https://doi.org/10.1016/j.ccr.2013.08.019

Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB. / Kuo, Hsu Ping; Wang, Zhong; Lee, Dung Fang; Iwasaki, Masayuki; Duque-Afonso, Jesus; Wong, Stephen H.K.; Lin, Chiou Hong; Figueroa, Maria; Su, Jie; Lemischka, Ihor R.; Cleary, Michael L.

In: Cancer Cell, Vol. 24, No. 4, 14.10.2013, p. 423-437.

Research output: Contribution to journalArticle

Kuo, HP, Wang, Z, Lee, DF, Iwasaki, M, Duque-Afonso, J, Wong, SHK, Lin, CH, Figueroa, M, Su, J, Lemischka, IR & Cleary, ML 2013, 'Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB', Cancer Cell, vol. 24, no. 4, pp. 423-437. https://doi.org/10.1016/j.ccr.2013.08.019
Kuo HP, Wang Z, Lee DF, Iwasaki M, Duque-Afonso J, Wong SHK et al. Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB. Cancer Cell. 2013 Oct 14;24(4):423-437. https://doi.org/10.1016/j.ccr.2013.08.019
Kuo, Hsu Ping ; Wang, Zhong ; Lee, Dung Fang ; Iwasaki, Masayuki ; Duque-Afonso, Jesus ; Wong, Stephen H.K. ; Lin, Chiou Hong ; Figueroa, Maria ; Su, Jie ; Lemischka, Ihor R. ; Cleary, Michael L. / Epigenetic Roles of MLL Oncoproteins Are Dependent on NF-κB. In: Cancer Cell. 2013 ; Vol. 24, No. 4. pp. 423-437.
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