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. 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.© 2024. The Author(s).

Res Ctr Nat Sci
CD-Labor für Immunmetabolismus und Systembiologie von Adipositas-bedingten Erkrankungen
CeMM Center for Molecular Medicine of the Austrian Academy of Sciences
University of Pécs
Università degli Studi di Torino
St. Anna Kinderspital GmbH
Medizinische Universität Wien - AKH
Semmelweis Egyetem
Österreichische Akademie der Wissenschaften
Medizinische Universität Graz
Karl Landsteiner Privatuniversität für Gesundheitswissenschaften GmbH
Veterinärmedizinische Universität Wien
University of Pecs
Semmelweis University
University of Turin
Hungarian Academy of Sciences