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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Proliferation
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Leukemic
  • HEK293 Cells
  • Hep G2 Cells
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / enzymology*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • THP-1 Cells
  • U937 Cells

Substances

  • Antineoplastic Agents
  • Histones
  • MEF2 Transcription Factors
  • MEF2C protein, human
  • Protein Kinase Inhibitors
  • Repressor Proteins
  • Protein Kinases
  • STK11 protein, human
  • salt-inducible kinase-2, human
  • Protein-Serine-Threonine Kinases
  • SIK3 protein, human
  • HDAC4 protein, human
  • Histone Deacetylases