Description
In acute myeloid leukemia (AML), around half of the patients demonstrate abnormal Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling, specifically STAT3, which is associated with poor clinical outcomes. STAT3, a key regulator of various cellular processes, is expressed in two alternatively spliced isoforms: the full-length isoform STAT3α and a shorter variant STAT3β. While STAT3α is generally linked to oncogenic activities, STAT3β has recently gained more attention for its anti-tumorigenic properties in various cancers.Earlier research identified STAT3β as playing a tumor-suppressive role in AML, with low STAT3β levels being linked to poor clinical outcomes. In this study we aimed to identify the underlying mechanism behind the protective role of STAT3β in AML, which could be exploited for therapeutic approaches.
To investigate this, we used an AML mouse model by transducing fetal liver cells of STAT3β-deficient and wildtype littermates with a vector encoding the fusion gene MLL-AF9, commonly found in AML patients, and transplanted intravenously into immunocompromised mice. To assess the impact of STAT3β loss, RNA sequencing was performed on leukemic cells isolated from diseased animals. In parallel, we analyzed diagnostic samples from AML patients, along with publicly available RNA sequencing data, to investigate STAT3β expression and correlated IFN-inducible gene expression with overall survival.
The absence of STAT3β significantly reduced survival in leukemic mice confirming its tumor suppressive role. Transcriptomic analysis revealed that STAT3β deficiency led to increased STAT1 expression and interferon (IFN) signaling. Furthermore, leukemia cells lacking STAT3β exhibited increased sensitivity to inhibition of IFN signaling, as demonstrated by reduced colony formation when treated either with an IFNAR1 blocking antibody or the JAK1/2 inhibitor ruxolitinib. In AML patient samples we observed a that elevated expression of STAT1 and IFN-inducible genes in linked to poorer overall survival and low STAT3β expression.
These results suggest patients with a low STAT3β/α mRNA ratio and poor prognosis may benefit from therapies targeting STAT1/IFN signaling.
| Period | 25 Mar 2025 → 28 Mar 2025 |
|---|---|
| Event title | 10th German Pharm-Tox Summit 2025 |
| Event type | Conference |
| Location | Hannover, GermanyShow on map |
| Degree of Recognition | International |