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Mol Cell. 2018 Mar 15;69(6):1017-1027.e6. doi: 10.1016/j.molcel.2018.02.011. Epub 2018 Mar 8.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Genetics Program, Stony Brook University, Stony Brook, NY 11794, USA.
3
Department of Cancer Biology, Abramson Family Cancer Research Institute, Epigenetics Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jushi@upenn.edu.
4
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address: vakoc@cshl.edu.

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.

KEYWORDS:

HDAC4; LKB1; MEF2C; MLL; SIK2; SIK3; acute myeloid leukemia; kinase; salt-inducible kinase; transcription

PMID:
29526696
PMCID:
PMC5856641
[Available on 2019-03-15]
DOI:
10.1016/j.molcel.2018.02.011
[Indexed for MEDLINE]
Free PMC Article

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