Mediator kinase phosphorylation of STAT1 S727 promotes growth of neoplasms with JAK-STAT activation Journal Article

Authors: Nitulescu, I. I.; Meyer, S. C.; Wen, Q. J.; Crispino, J. D.; Lemieux, M. E.; Levine, R. L.; Pelish, H. E.; Shair, M. D.
Article Title: Mediator kinase phosphorylation of STAT1 S727 promotes growth of neoplasms with JAK-STAT activation
Abstract: Constitutive JAK-STAT signaling drives the proliferation of most myeloproliferative neoplasms (MPN) and a subset of acute myeloid leukemia (AML), but persistence emerges with chronic exposure to JAK inhibitors. MPN and post-MPN AML are dependent on tyrosine phosphorylation of STATs, but the role of serine STAT1 phosphorylation remains unclear. We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. Inhibition of serine phosphorylation by CA promotes growth arrest and differentiation, inhibits colony formation in MPN patient samples and reduces allele burden in MPN mouse models. These results reveal that STAT1 pS727 regulates growth and differentiation in JAK-STAT activated neoplasms and suggest that Mediator kinase inhibition represents a therapeutic strategy to regulate JAK-STAT signaling. © 2017
Keywords: signal transduction; protein phosphorylation; leukemia; nonhuman; flow cytometry; cell proliferation; animal cell; mouse; stat1 protein; bone marrow; animal experiment; animal model; cell differentiation; janus kinase; western blotting; immunoprecipitation; plasmid; upregulation; cell density; cortistatin; protein kinase; myeloproliferative neoplasm; kinase inhibitor; colony formation; acute myeloid leukemia; cortistatin a; ruxolitinib; mpn; priority journal; article; cell growth assay; crispr associated protein; stat1; crispr-cas9 system; cdk8; super-enhancer
Journal Title: EBioMedicine
Volume: 26
ISSN: 2352-3964
Publisher: Elsevier Inc.  
Date Published: 2017-12-01
Start Page: 112
End Page: 125
Language: English
DOI: 10.1016/j.ebiom.2017.11.013
PROVIDER: scopus
PUBMED: 29239838
PMCID: PMC5832629
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Ross Levine
    508 Levine
  2. Sara Christina Meyer
    9 Meyer