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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Edtmayer, S; Witalisz-Siepracka, A; Zdársky, B; Heindl, K; Weiss, S; Eder, T; Dutta, S; Graichen, U; Klee, S; Sharif, O; Wieser, R; Győrffy, B; Poli, V; Casanova, E; Sill, H; Grebien, F; Stoiber, D.
A novel function of STAT3β in suppressing interferon response improves outcome in acute myeloid leukemia.
Cell Death Dis. 2024; 15(5): 369
Doi: 10.1038/s41419-024-06749-9
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- Co-authors Med Uni Graz
- Dutta Sayantanee
- Sill Heinz
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Leukemia, Myeloid, Acute - genetics, pathology, metabolism
- Humans - administration & dosage
- STAT3 Transcription Factor - metabolism
- Mice - administration & dosage
- Signal Transduction - administration & dosage
- Interferons - metabolism
- STAT1 Transcription Factor - metabolism, genetics
- Mice, Inbred C57BL - administration & dosage
- Receptor, Interferon alpha-beta - metabolism, genetics
- Cell Line, Tumor - administration & dosage
- Nitriles - administration & dosage
- Pyrazoles - administration & dosage
- Pyrimidines - administration & dosage