NF-κB functions upstream of MLL oncoproteins and sustains MLL-mediated leukemogenesis.

  • Major finding: NF-κB functions upstream of MLL oncoproteins and sustains MLL-mediated leukemogenesis.

  • Mechanism: RELA recruits MLL oncoproteins and regulates transcription at MLL target gene promoters.

  • Impact: Inhibitors of the NF-κB pathway may be particularly effective in MLL-rearranged leukemia.

The mixed-lineage leukemia (MLL) gene encodes a histone H3 lysine 4 (H3K4) methyltransferase that regulates hematopoietic gene expression. Chromosomal rearrangements that generate MLL fusions lead to deregulation of MLL target genes and cause aggressive leukemias. The transcriptional and epigenetic consequences of MLL fusion protein activity are well studied, but little is known about the upstream pathways that cooperate with MLL in leukemogenesis. Kuo and colleagues performed an shRNA screen of kinases and phosphatases to identify those required for MLL-transformed myeloid progenitor growth and noted multiple NF-κB pathway components among the top-scoring hits. Consistent with these results, MLL-rearranged leukemia cell lines were more sensitive to inhibitors of IκB kinase (IKK), an upstream activator of NF-κB signaling, than non–MLL-rearranged leukemia cells. IKK inhibition more significantly inhibited growth and clonogenicity in MLL-transformed myeloid progenitors than in non–MLL-transformed or normal myeloid progenitors, further pointing to a specific requirement for NF-κB signaling in the oncogenic activity of MLL. Inhibition of IKK also significantly reduced the proliferation and survival of MLL-rearranged leukemia cells, induced their differentiation, and decreased leukemic stem cell potential in colony-forming and secondary transplantation assays. Knockdown of the NF-κB protein RELA (also known as p65) similarly inhibited MLL-rearranged leukemia cell growth and transformation, and RELA was required for the initiation and maintenance of MLL-rearranged leukemia in vivo. RELA directly bound the promoters of the key oncogenic MLL targets HoxA9 and Meis1 in murine acute leukemia cells, and IKK inhibition decreased MLL fusion protein occupancy and H3K79 methylation levels at the HoxA9 and Meis1 promoters and reduced HoxA9 and Meis1 expression. The identification of the NF-κB pathway as an upstream regulator of oncogenic MLL activity raises the possibility that targeted inhibition of NF-κB signaling may be especially effective in MLL-rearranged leukemias.

Kuo HP, Wang Z, Lee DF, Iwasaki M, Duque-Afonso J, Wong SH, et al. Epigenetic roles of MLL oncoproteins are dependent on NF-κB. Cancer Cell 2013 Sept 19 [Epub ahead of print].