PS982 THE ROLE OF STAT3 ISOFORMS IN ACUTE MYELOID LEUKEMIA

• Published in: HemaSphere Vol. 3; no. S1; pp. 441 - 442
• Main Authors: Aigner, P., Mizutani, T., Horvath, J., Just, V., Sill, H., Grebien, F., Moriggl, R., Casanova, E., Stoiber, D.
• Format: Journal Article
• Language: English
• Published: 01.06.2019
• ISSN: 2572-9241; 2572-9241
• DOI: 10.1097/01.HS9.0000562228.80333.3e

Background: Signal transducer and activator of transcription 3 (STAT3) plays a central role in proliferation, differentiation and oncogenic transformation. It is expressed in two alternatively spliced isoforms, STAT3α and truncated STAT3β, which lacks the C‐terminal transactivation domain and instead carries seven unique amino acids. Interestingly, STAT3β recently gained attention as a powerful anti‐tumorigenic molecule and protective prognostic marker. This has been shown in patients with esophageal squamous cell carcinoma as well as in mouse models for breast, skin and colon cancer. Deregulated STAT3 signaling is frequently observed in leukemogenesis and generally associated with a poor clinical outcome in patients with acute myeloid leukemia (AML). In addition, it has been shown that the expression ratios of STAT3α and STAT3β change upon myeloid differentiation. However, the exact role of STAT3β in AML patients and during disease progression remains unknown. Aims: The goal of our study is to analyze the contribution of the two STAT3 isoforms to leukemogenesis with a particular focus on STAT3β in AML development. Methods: We analyzed more than 50 AML patient samples for STAT3β/STAT3α mRNA expression levels and its correlation with clinical prognosis and overall survival. Furthermore, we generated an inducible Stat3β transgenic mouse model and crossed it with Pten‐deficient mice, a previously described model for AML. In addition, we used fetal liver‐derived stem cells from Stat3β transgenic mice, transduced with a retrovirus encoding for the MLL‐AF9 translocation, in a transplant model for AML. Results: We observed a correlation between clinical prognosis and STAT3β/STAT3α expression ratio. A higher STAT3β/STAT3α ratio was further associated with a favorable clinical prognosis and a significantly increased overall survival. In both in vivo mouse models we could demonstrate that the expression of STAT3β impairs leukemogenesis and leukemic cell infiltration into hematopoietic organs. The STAT3β‐dependent delay in disease progression and leukemic infiltration resulted in a significant increase of overall survival. Summary/Conclusion: In summary, the results of our study demonstrate STAT3β as an anti‐tumorigenic molecule in AML mouse models and the STAT3β/STAT3α ratio in AML patient derived blasts positively correlates with survival.