The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy.

Academic Article

Abstract

  • To identify novel therapeutic targets in acute myeloid leukemia (AML), we examined kinase expression patterns in primary AML samples. We found that the serine/threonine kinase IKBKE, a noncanonical IkB kinase, is expressed at higher levels in myeloid leukemia cells compared with normal hematopoietic cells. Inhibiting IKBKE, or its close homolog TANK-binding kinase 1 (TBK1), by either short hairpin RNA knockdown or pharmacological compounds, induces apoptosis and reduces the viability of AML cells. Using gene expression profiling and gene set enrichment analysis, we found that IKBKE/TBK1-sensitive AML cells typically possess an MYC oncogenic signature. Consistent with this finding, the MYC oncoprotein was significantly downregulated upon IKBKE/TBK1 inhibition. Using proteomic analysis, we found that the oncogenic gene regulator YB-1 was activated by IKBKE/TBK1 through phosphorylation, and that YB-1 binds to the MYC promoter to enhance MYC gene transcription. Momelotinib (CYT387), a pharmacological inhibitor of IKBKE/TBK1, inhibits MYC expression, reduces viability and clonogenicity of primary AML cells, and demonstrates efficacy in a murine model of AML. Together, these data identify IKBKE/TBK1 as a promising therapeutic target in AML.
  • Authors

  • Liu, Suhu
  • Marneth, Anna E
  • Alexe, Gabriela
  • Walker, Sarah
  • Gandler, Helen I
  • Ye, Darwin Q
  • Labella, Katherine
  • Mathur, Radhika
  • Toniolo, Patricia A
  • Tillgren, Michelle
  • Gokhale, Prafulla C
  • Barbie, David
  • Mullally, Ann
  • Stegmaier, Kimberly
  • Frank, David A
  • Status

    Publication Date

  • December 11, 2018
  • Published In

  • Blood Adv  Journal
  • Keywords

  • Animals
  • Apoptosis
  • Benzamides
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Down-Regulation
  • Humans
  • I-kappa B Kinase
  • Leukemia, Myeloid, Acute
  • Mice
  • Mice, Inbred NOD
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • Proteomics
  • Proto-Oncogene Proteins c-myc
  • Pyrimidines
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Y-Box-Binding Protein 1
  • Digital Object Identifier (doi)

    Start Page

  • 3428
  • End Page

  • 3442
  • Volume

  • 2
  • Issue

  • 23