A novel function of STAT3β in suppressing interferon response improves outcome in acute myeloid leukemia.
Sophie EdtmayerAgnieszka Witalisz-SieprackaBernhard A MoserKerstin HeindlStefanie WeissThomas EderSayantanee DuttaUwe GraichenSascha KleeOmar SharifRotraud WieserBalázs GyőrffyValeria PoliEmilio CasanovaHeinz SillFlorian GrebienDagmar StoiberPublished in: Cell death & disease (2024)
Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3β. While STAT3α is predominantly described as an oncogenic driver, STAT3β has been suggested to act as a tumor suppressor. To elucidate the role of STAT3β in AML, we established a mouse model of STAT3β-deficient, MLL-AF9-driven AML. STAT3β deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3β. Accordingly, STAT3β-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3β expression. Together, our data corroborate the tumor suppressive role of STAT3β in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3β/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3β/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.
Keyphrases
- acute myeloid leukemia
- cell proliferation
- mouse model
- immune response
- poor prognosis
- type diabetes
- end stage renal disease
- chronic kidney disease
- atrial fibrillation
- small molecule
- adipose tissue
- toll like receptor
- insulin resistance
- inflammatory response
- binding protein
- single cell
- prognostic factors
- skeletal muscle
- long non coding rna
- social media
- health information
- artificial intelligence