The kinases IKBKE and TBK1 regulate MYC-dependent survival pathways through YB-1 in AML and are targets for therapy
Open accessAbstract
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.
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hnRNP K, SRSF3, and YB-1 show altered expression in AML and contribute to leukemia progression.
“In addition, the expression of hnRNP K (40), SRSF3 (SRp20) (41), and YB-1 (42) has been shown to be altered in AML, but also to contribute to leukemia progression.”
From Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias (2021) · cites this paper as [42]
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Mäkelä, E., Pavic, K., Varila, T., Salmenniemi, U., Löyttyniemi, E., Nagelli, S. G., Ammunét, T., Kähäri, V.-M., Clark, R. E., Elo, L. L., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3679 · Cited by 18 · see citing works
- Authors
- Liu, S., Marneth, A. E., Alexe, G., Walker, S. R., Gandler, H. I., Ye, D. Q., Labella, K., Mathur, R., Toniolo, P. A., Tillgren, M., Gokhale, P. C., Barbie, D., Mullally, A., Stegmaier, K., & Frank, D. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Department of Pediatric Oncology and
- Dana-Farber Cancer Institute (US)
- Broad Institute (US)
- ORCID
- Venue
- Blood Advances
- Publisher
- American Society of Hematology
- Published
- 2018-11-30
- Volume
- 2
- Issue
- 23
- Pages
- 3428-3442
- ISSN
- 2473-9529 (ISSN-L)
- 2473-9537
- PMC
- PMC6290107
- OpenAlex
- W2903213274
- Cited by
- 33
- References
- 38
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 8 · 2020: 3 · 2019: 2
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Blood Advances (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL131835, T32HL116324)
- National Cancer Institute (R01CA160979, R35CA210030)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- acute myeloid leukemia, IKBKE, TBK1, YB-1, c-Myc, kinase inhibition, momelotinib, apoptosis, therapeutic target
- MeSH terms
- Animals, Benzamides, Humans, Phosphorylation, Pyrimidines, Biomarkers, Tumor, Signal Transduction, Leukemia, Myeloid, Acute, Down-Regulation, Proto-Oncogene Proteins c-myc, Mice, Inbred NOD, Apoptosis, Protein Serine-Threonine Kinases, RNA Interference, RNA, Small Interfering, Proteomics, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, I-kappa B Kinase, Y-Box-Binding Protein 1
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