cortistatin-a and Leukemia--Myeloid--Acute

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.

Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Humans; Janus Kinase 2; Leukemia, Myeloid, Acute; Mice; Nitriles; Phosphorylation; Polycyclic Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction; STAT1 Transcription Factor

Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6-8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.

Topics: Animals; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Cell Lineage; Cyclin-Dependent Kinase 8; Cyclin-Dependent Kinases; Disease Progression; Down-Regulation; Enhancer Elements, Genetic; Female; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genes, Tumor Suppressor; Heterocyclic Compounds, 4 or More Rings; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred Strains; Mice, SCID; Nuclear Proteins; Polycyclic Compounds; Transcription Factors; Up-Regulation

A new compound with anti-leukemia activity perturbs gene transcription by modulating super-enhancer activity.

Topics: Cell Proliferation; Cyclin-Dependent Kinases; Humans; Leukemia, Myeloid, Acute; Polycyclic Compounds; Protein Kinase Inhibitors; Transcription, Genetic