Pb1805: breaking a paradigm: loss of stat3 increases invasion in mll-af9-driven acute myeloid leukemia

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Deregulated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a heterogenous disease with poor prognosis. In 44% of AML patients, STAT3 displays constitutive activity which is associated with short disease-free survival. Various strategies for selective targeting of JAK-STAT signaling have demonstrated promising results in vitro and in vivo with some compounds reaching clinical trials for AML. However, several drug candidates have failed to provide therapeutic benefit, which is probably due to the heterogenicity behind AML development and progression. Aims: The goal of the present study is to investigate the detailed molecular mechanisms of STAT3 in AML development. Furthermore, we want to evaluate its role in the progression of different AML subtypes and to identify STAT3-targets that could be potential therapeutic molecules. Methods: Using CRISPR/Cas9 we generated STAT3-deficient human AML cell lines. The cell lines were characterized via flow cytometry, Western blot and qPCR and used for transplantation via tail vein into immunocompromised NSG mice. Results: AML cells lacking STAT3 showed no major impairment in survival and proliferation under basal conditions in vitro. STAT3 knockout (KO) AML (M6) HEL cells were less resistant to different drug treatments, whereas AML (M5) THP-1 STAT3 KO cells were generally more resistant. Interestingly, loss of STAT3 in THP-1 cells increased ZEB-1 and CXCR4 expression, two essential regulators of epithelial mesenchymal transition (EMT), cell migration and invasion. Animals transplanted with STAT3-deficient THP-1 cells showed accelerated disease progression, poorer overall survival, and increased liver infiltration, whereas there was no difference between the control group and mice injected with STAT3 KO HEL cells. Summary/Conclusion: We uncovered a paradigm shift in understanding the key function of STAT3 in metastatic progression in AML, which might be an explanation for the diverse treatment outcomes in patients. Our data indicate a surprising novel role of STAT3 in regulating invasive infiltration in MLL-AF9-driven AML. As a next step, we aim to identify AML subgroups that would benefit from therapeutical inhibition of STAT3 targets, in which STAT3 and e.g., ZEB-1 and CXCR4 act as prognostic marker for risk stratification, avoiding both over- and undertreatment of AML patients. Keywords: Acute myeloid leukemia, Metastasis, STAT3, Liver