STAT3 Isoformen in hämatopoetischen Erkrankungen
Lead partner:
Karl Landsteiner Privatuniversität für Gesundheitswissenschaften
Scientific management:
Dagmar Stoiber-Sakaguchi
Additional participating institutions:
Universitätsklinikum Krems
Medizinische Universität Wien
Research field:
Krebsforschung
Funding tool: Basic research projects
Project-ID: LS19-019
Project start: 01. Jänner 2021
Project end: will follow
Runtime: 36 months / ongoing
Funding amount: € 290.000,00
Brief summary:
Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is frequently associated with tumor development and the constitutive activation of STATs lies at the root of different hematopoietic malignancies. While several STAT members have been described to act as oncogenes, the transcription factor STAT3 serves as paradigm for tumorigenic signaling within this family. STAT3 has been described to promote proliferation as well as differentiation and it is the loss of transcriptional targets associated with differentiation, which is linked to the acquisition of tumorigenic potential. However, the underlying molecular mechanisms are still incompletely understood. Stat3 produces two isoforms (STAT3? and ?) by alternative splicing that exhibit overlapping but distinct transcriptional activity. Both are selectively expressed and activated in leukemic but also in normal human CD34 positive immature cells in the bone marrow. Of note, the ratio of the two isoforms changes during cell differentiation. Thereby, the balance of the two alternatively spliced STAT3 isoforms may contribute to leukemia development.
The goal of this project is to analyze the contribution of STAT3 isoforms to hematopoietic disorders. Pilot experiments using Stat3? transgenic mice revealed that in leukemia mouse models the STAT3? transgene leads to delayed disease progression and significantly increased survival. Hence, we plan to investigate how the shorter isoform, STAT3?, acts as tumor suppressor during acute myeloid leukemia and whether it has a similar role in myelodysplastic syndrome as well as multiple myeloma. Furthermore, we aim to elucidate whether the balance of the two isoforms may help to predict patient outcome. This study is expected to shed light on the function of the shorter isoform STAT3? and STAT3-mediated control of leukocytes.
Keywords:
Pharmacology, Immunology, Molecular Biology