Background: Signal transducer and activator of transcription 3 (STAT3) is a mediator of cytokine signaling existing in two alternatively spliced isoforms known as the full-length isoform STAT3α (770aa) and the C-terminally truncated isoform STAT3β (722aa). Initially STAT3β was described as the dominant negative form of STAT3α. It gained more attention as it turned out to initiate transcription independent of STAT3α and being capable to rescue embryonic lethality in absence of STAT3α. In acute myeloid leukemia (AML) patients, STAT3 has been reported to be constitutively activated thereby promoting proliferation and blast survival. However, most of those studies did not consider the two distinct isoforms of STAT3. Recently, our group identified STAT3β as a novel tumor suppressor and favorable prognostic marker in AML, however the underlying mechanism in leukemic cells remained elusive.
Aims: With this study we aim to provide in-depth knowledge on the role of STAT3 isoforms in AML development and disease outcome.
Methods: By using murine AML cell lines lacking either STAT3α or STAT3β, we aim to elucidate the STAT3 isoform-specific impact on cellular processes shaping AML development and progression. To gain better understanding we use AML in vivo models and in vitro assays in combination with next-generation sequencing (NGS) approaches to identify molecular mechanisms explaining the tumor suppressive function of STAT3β in AML. In brief, fetal liver-derived stem cells, isolated from STAT3α and STAT3β deficient mice on C57BL/6J background, were transduced with a retrovirus introducing the human fusion-oncogene MLL-AF9, and intravenously transplanted into immunocompromised mice.
Results: Animals transplanted with leukemic cells lacking STAT3β showed accelerated disease progression and poorer overall survival confirming its tumor suppressive properties. Furthermore, absence of STAT3β favored leukemic infiltration and migration. Additionally, RNA sequencing revealed that lack of STAT3β in leukemic cells leads to a dysregulation of crucial genes driving leukemogenesis.
Summary/Conclusion: Understanding the mechanisms behind the tumor suppressive property of STAT3β has potential translational impact and is crucial to identify novel therapies and preventative strategies. Further validation and ChIP sequencing will provide novel direct target genes of STAT3β which could serve as prognostic or therapeutic molecules.
