Titel (eng)

A novel function of STAT3? in suppressing interferon response improves outcome in acute myeloid leukemia

Autor*in

Sophie Edtmayer   Karl Landsteiner University of Health Sciences

Dagmar Stoiber   Karl Landsteiner University of Health Sciences

Florian Grebien   University of Veterinary Medicine Vienna / Austrian Academy of Sciences

Heinz Sill   Medical University of Graz

Emilio Casanova   Medical University of Vienna

Valeria Poli   University of Turin

Balázs Gyorffy   Semmelweis University / University of Pecs

Rotraud Wieser   Medical University of Vienna

Omar Sharif   Medical University of Vienna

Sascha Klee   Karl Landsteiner University of Health Sciences

Uwe Graichen   Karl Landsteiner University of Health Sciences

Sayantanee Dutta   Medical University of Graz

Thomas Eder   University of Veterinary Medicine Vienna

Stefanie Weiss   Karl Landsteiner University of Health Sciences

Kerstin Heindl   Karl Landsteiner University of Health Sciences

Agnieszka Witalisz-Siepracka   Karl Landsteiner University of Health Sciences

Bernhard Zdársky   Karl Landsteiner University of Health Sciences

Verlag

Springer Nature

Beschreibung (eng)

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.

Sprache des Objekts

Englisch

Datum

2024

Rechte

Dieses Werk bzw. dieser Inhalt steht unter einer
CC BY 4.0 - Creative Commons Namensnennung 4.0 International Lizenz.

CC BY 4.0 International

http://creativecommons.org/licenses/by/4.0/

Klassifikation

Animals; Leukemia, Myeloid, Acutegeneticspathologymetabolism; Humans; STAT3 Transcription Factormetabolism; Mice; Signal Transduction; Interferonsmetabolism; STAT1 Transcription Factormetabolismgenetics; Mice, Inbred C57BL; Receptor, Interferon alpha-betametabolismgenetics; Cell Line, Tumor; Nitriles; Pyrazoles; Pyrimidines

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