Tonic interferon signaling in acute myeloid leukemia cells is associated with adverse disease outcome

Background
Aberrant JAK/STAT activation is commonly observed in acute myeloid leukemia (AML), with constitutive STAT3 activation particularly associated with poor disease outcomes. However, pharmacological targeting STAT3 has shown only modest efficacy. One potential explanation is the existence of two distinct STAT3 isoforms produced by alternative splicing: the oncogenic full-length isoform STAT3α and the truncated isoform STAT3β, which has reported tumor-suppressive properties.
In a recent study, we uncovered a link between STAT3 isoform expression and interferon (IFN) signaling in AML cells that influence disease outcome. Specifically, the absence of STAT3β led to increased IFN signaling and was associated with worse outcome in an AML mouse model and reduced patient survival rates. Notably, inhibition of IFN signaling using JAK inhibitors exposed a vulnerability of leukemia cells reliant on tonic IFN signaling, suggesting a potential therapeutic strategy.
Aims
This study aims to reveal how tonic IFN signaling in leukemia cells influences disease outcome. Pharmacological targeting of IFN signaling could offer a promising therapeutic approach.
Methods
Diagnostic samples from patients with AML were analyzed using RT-qPCR, complemented by publicly available RNA sequencing data to examine the correlation between IFN-inducible genes and overall survival. In an AML mouse model, hematopoietic stem cells from either the fetal liver or the bone marrow were retrovirally transduced with a vector encoding the MLL-AF9 fusion gene. These transformed cells were then intravenously transplanted into immunodeficient mice for survival analysis. Leukemia cells were isolated from diseased animals for RNA sequencing, and plasma samples were assessed using a cytokine multiplex assay.
Results
Analysis of patient samples revealed that the elevated expression of IFN-inducible genes (e.g., STAT1, GB2, GBP4, UBE2L6) correlates with shorter overall survival. Leukemia cells lacking the tumor suppressor STAT3β showed enhanced IFN signaling both in vitro and when transplanted into immunodeficient mice which correlated with a more aggressive disease phenotype. Furthermore, higher concentrations of IFNγ were found in the plasma of mice with shorter survival. Collectively, these findings suggest that heightened IFN signaling is linked to poorer disease outcomes. In this study, we investigate the effects of IFNγ deficiency and IFNAR1 knockout in AML cells to explore how tonic IFN signaling influences the disease progression.
Summary Conclusion
Based on our findings so far, AML patients with aberrant JAK/STAT signaling and elevated IFN signaling might benefit from treatment combinations that include the JAK1/2 inhibitor Ruxolitinib.