A novel function of STAT3β in suppressing interferon response improves outcome in acute myeloid leukemia

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 STAT3 alpha and the C-terminally truncated isoform STAT3 beta. While STAT3 alpha is predominantly described as an oncogenic driver, STAT3 beta has been suggested to act as a tumor suppressor. To elucidate the role of STAT3 beta in AML, we established a mouse model of STAT3 beta-deficient, MLL-AF9-driven AML. STAT3 beta 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 STAT3 beta. Accordingly, STAT3 beta-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 STAT3 beta expression. Together, our data corroborate the tumor suppressive role of STAT3 beta 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 STAT3 beta/alpha mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3 beta/alpha mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.