Tarumoto, Y., Lu, B., Somerville, T. D. D., Huang, Y. H., Milazzo, J. P., Wu, X. S., Klingbeil, O., El Demerdash, O., Shi, J., Vakoc, C. R. (March 2018) LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. Mol Cell, 69 (6). pp. 1017-1027. ISSN 1097-2765
Abstract
The lineage-specific transcription factor (TF) MEF2C is often deregulated in leukemia. However, strategies to target this TF have yet to be identified. Here, we used a domain-focused CRISPR screen to reveal an essential role for LKB1 and its Salt-Inducible Kinase effectors (SIK3, in a partially redundant manner with SIK2) to maintain MEF2C function in acute myeloid leukemia (AML). A key phosphorylation substrate of SIK3 in this context is HDAC4, a repressive cofactor of MEF2C. Consequently, targeting of LKB1 or SIK3 diminishes histone acetylation at MEF2C-bound enhancers and deprives leukemia cells of the output of this essential TF. We also found that MEF2C-dependent leukemias are sensitive to on-target chemical inhibition of SIK activity. This study reveals a chemical strategy to block MEF2C function in AML, highlighting how an oncogenic TF can be disabled by targeting of upstream kinases.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Hdac4 Lkb1 Mef2c Mll Sik2 Sik3 acute myeloid leukemia kinase salt-inducible kinase transcription |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase diseases & disorders > cancer > cancer types > leukemia |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Gene Regulation and Cell Proliferation CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program |
| Depositing User: | Matt Covey |
| Date: | 15 March 2018 |
| Date Deposited: | 19 Mar 2018 14:50 |
| Last Modified: | 05 Nov 2020 16:58 |
| PMCID: | PMC5856641 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36277 |
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