THE ROLE OF STAT3 ISOFORMS IN ACUTE MYELOID LEUKEMIA
Author(s): ,
Petra Aigner
Affiliations:
Institute of Pharmacology,Medical University of Vienna,Vienna,Austria
,
Tatsuaki Mizutani
Affiliations:
Ludwig Boltzmann Institute for Cancer Research,Vienna,Austria
,
Jaqueline Horvath
Affiliations:
Medical University of Vienna,Vienna,Austria
,
Valentin Just
Affiliations:
University of Veterinary Medicine, Vienna,Vienna,Austria
,
Heinz Sill
Affiliations:
Medical University of Graz,Graz,Austria
,
Florian Grebien
Affiliations:
University of Veterinary Medicine Vienna,Vienna,Austria
,
Richard Moriggl
Affiliations:
University of Veterinary Medicine, Vienna,Vienna,Austria
,
Emilio Casanova
Affiliations:
Department of Physiology,Medical University of Vienna,Vienna,Austria
Dagmar Stoiber
Affiliations:
Karl Landsteiner University of Health Sciences,Krems,Austria
EHA Library. Stoiber D. Jun 15, 2019; 267283; PS982
Dagmar Stoiber
Dagmar Stoiber
Contributions
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Abstract

Abstract: PS982

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

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.

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.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Leukemogenesis, STAT3, Tumor suppressor

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