Epigenetic roles of MLL oncoproteins are dependent on NF-κB.
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.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Hsu-Ping
HP
Kuo
Zhong
Z
Wang
Dung-Fang
DF
Lee
Masayuki
M
Iwasaki
Jesus
J
Duque-Afonso
Stephen H K
SH
Wong
Chiou-Hong
CH
Lin
Maria E
ME
Figueroa
Jie
J
Su
Ihor R
IR
Lemischka
Michael L
ML
Cleary
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D002843:Chromatin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D023281:Genomics; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic
D002843:Chromatin; C497422:KMT2A protein, human; D016328:NF-kappa B; D051996:Transcription Factor RelA; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D051550:I-kappa B Kinase