LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia

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

URL: https://www.ncbi.nlm.nih.gov/pubmed/29526696
DOI: 10.1016/j.molcel.2018.02.011

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 labs > Vakoc lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date: 15 March 2018
Date Deposited: 19 Mar 2018 14:50
Last Modified: 12 Jun 2018 19:25
PMCID: PMC5856641
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36277

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving