MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia

Abstract

In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease. Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. .

Downregulation of circulating miR 802‐5p and miR 194‐5p and upregulation of brain MEF2C along breast cancer brain metastasization

“…These observations provide a basis for further studying the contribution of MEF2C to the brain metastatic process and the underlying signaling pathways. It would also be interesting to analyze whether MEF2C is phosphorylated as reported in acute myeloid leukemia where phosphorylation appeared to induce apoptosis resistance and its inhibition reverted chemotherapy resistance (Brown et al , ). Moreover, by revealing MEF2C in BCBM, they point to the relevance of further studying this transcription factor both as a prognostic biomarker and as a potential target for modulation.…”

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia

“…Alternative bHLH transcription factors may cooperate with MYB in some leukemia subtypes (Jones, 2004). It will be important to determine how aberrant co-expression of such oncogenic regulatory complex co-factors is induced in leukemia cells, such as for example by kinase-dependent dysregulation of transcription factor assembly for MEF2C and LYL1 (Brown et al, 2018;Tarumoto et al, 2018;Vakoc and Kentsis, 2018). It will also be interesting to examine whether resistance of erythroblastic BRC-ABL1-translocated K562 cells to CRYBMIM represents a solitary case, or portends lack of dependence on MYB by BCR-ABL1 fusion or erythroid leukemias.…”

“…While specific molecular dependencies have been identified for some genetic subtypes of AML, such as DOT1L or Menin inhibition for MLL-rearranged leukemias (Krivtsov et al, 2019), and CARM1 inhibition for AML1-rearranged leukemias (Greenblatt et al, 2019), distinct pathogenetic mechanisms of diverse AML subtypes also appear to converge on shared molecular pathways. For example, approximately 25% of adult and childhood AMLs, including both MLLrearranged and non-rearranged cases, require aberrant activation of the transcription factor MEF2C, conferring susceptibility to MARK and SIK inhibitors, which are currently being explored for clinical trials for patients (Brown et al, 2018;Tarumoto et al, 2018;Vakoc and Kentsis, 2018). Similarly, nearly 50% of examined AML specimens exhibit aberrant activation of HGF/MET/FGFR signaling (Kentsis et al, 2012), as being currently tested in the ongoing clinical trial of combined MET and FGFR inhibitors in patients with relapsed or refractory AML (ClinicalTrials.gov Identifier NCT03125239).…”

The potent roles of salt-inducible kinases (SIKs) in metabolic homeostasis and tumorigenesis

“… 8 MRT-199665 inhibits SIK-mediated CRTC3 phosphorylation to increase LPS-stimulated IL-10 production and inhibit the secretion of proinflammatory cytokines, such as IL-6, IL-12, and TNFα in macrophages. 8 , 85 MRT-199665 can also induce apoptosis of human acute myeloid leukemia cells by activating MEF2C in vitro, 157 and enhance TGF-β-mediated apoptosis and death of murine mammary epithelial cells. 85 YKL-06-061 and YKL-06-062 are employed as selective second-generation inhibitors of SIKs.…”