Abstract
MEF2C activity in acute myeloid leukemia is dependent upon salt-inducible kinase (SIK) signaling.
Major finding: MEF2C activity in acute myeloid leukemia is dependent upon salt-inducible kinase (SIK) signaling.
Approach: CRISPR/Cas9-based screening identified essential protein kinase domains in 26 human cancer cell lines.
Impact: Chemical inhibition of SIKs is a potential therapeutic approach for patients with AML.
Mixed-lineage leukemia (MLL) fusion oncoproteins in acute myeloid leukemia (AML) drive the upregulation of the transcription factor MEF2C, which is required for the lineage specification process during hematopoiesis and the development of other cell types as well as AML progression. Because transcription factors are difficult to therapeutically target, Tarumoto and colleagues employed a kinase domain–focused CRISPR screen of 26 human cancer cell lines, including 8 AML cell lines, to identify AML-specific kinase dependencies. CRISPR/Cas9 screening of 482 kinase domains showed that MLL fusion–expressing AML cell lines were hypersensitive to loss of serine/threonine kinase 11 (also known as LKB1 and encoded by STK11) and the AMPK-related kinase salt-inducible kinase 3 (SIK3), and CRISPR/Cas9-targeted depletion of SIK3 in NIH373 cells and MLL fusion AML cells resulted no changes in growth in the former and decreased proliferation in the latter. Activation of SIK3 is dependent on the phosphorylation of the T221 residue by LKB1, and the T221A mutation resulted in decreased proliferation of MLL fusion AML cells. Concomitant CRISPR/Cas9 targeting of SIK3 and one of its known targets identified HDAC4 as the critical target of SIK3 in AML, and chromatin immunoprecipitation–sequencing analyses revealed that LKB1 and SIK3 are essential for preventing HDAC4-mediated deacetylation of MEF2C-bound enhancer elements in human MLL fusion AML cell lines. Consistent with these findings, depletion of LKB1 or SIK3 resulted in the significantly decreased expression of the MEF2C gene signature in leukemia cells expressing both MEF2C and HDAC4 but not in leukemia cells that were deficient of HDAC4 or both HDAC4 and MEF2C. Together, these results characterize the role of SIKs in AML and identify a strategy by which transcription factors can be therapeutically targeted in cancers.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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