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

• Published in: Cell death & disease Vol. 15; no. 5; p. 369
• Main Authors: Edtmayer, Sophie, Witalisz-Siepracka, Agnieszka, Zdársky, Bernhard, Heindl, Kerstin, Weiss, Stefanie, Eder, Thomas, Dutta, Sayantanee, Graichen, Uwe, Klee, Sascha, Sharif, Omar, Wieser, Rotraud, Győrffy, Balázs, Poli, Valeria, Casanova, Emilio, Sill, Heinz, Grebien, Florian, Stoiber, Dagmar
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.05.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/21; 13/31; 13/95; 38/91; 631/67/1990/283/1897; 64/60; 692/699/67/1244; 82/80; 96/2; Acute myeloid leukemia; Alternative splicing; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Blocking antibodies; Cell Biology; Cell Culture; Cell Line, Tumor; Humans; Immunology; Interferon; Interferons - metabolism; Isoforms; Janus kinase; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Life Sciences; Medical prognosis; Mice; Mice, Inbred C57BL; Nitriles; Pyrazoles; Pyrimidines; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; Signal Transduction; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Stat3 protein; STAT3 Transcription Factor - metabolism; Therapeutic applications; Tumor suppressor genes; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06749-9

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.