Acute myeloid leukaemia (AML) accounts for approximately 25% of all adult leukemias. The current standard of care for AML involves initiation and consolidation chemotherapy followed by stem cell transplantation. Responses to this therapy vary however and, even if effective, most patients will relapse within 2-3 years. With many patients being elderly there is also a substantial number who do not tolerate current treatment methods.
The t(8;21) translocation resulting in the expression of the AML1-ETO fusion protein is present in up to 15% of AML. Deregulated epigenetic activity via the recruitment of histone deacetylases (HDACs) by AML1-ETO is critical to the onset and progression of this disease. Thus the use of targeted therapies such as DAC inhibitors (DACi) may result in clinical benefit. We performed in vivo studies using a mouse model of t(8:21) AML to investigate the mechanisms by which DACi can effectively treat this disease. Our data indicate that DACi’s induce degradation of AML1-ETO accompanied by cell cycle arrest and cellular differentiation. We then further investigated the efficacy of combining this drug with other therapeutic agents.
Arsenic trioxide is extremely effective in targeting leukemic blasts in promyelocytic leukemia when used in combination with retinoic acid, leading to differentiation and apoptosis. Based on this, we tested the ability of this drug in our AML model in combination with DACi to target DACi-resistant leukemic blasts and improve overall survival. By combining arsenic trioxide with DACi we observed accelerated differentiation, increased levels of apoptosis and in a proportion of mice, a significantly extended survival compared to treatment with DACi alone. This provides the first pre-clinical evidence that combination therapies utilising DACi-induced differentiation of tumor cells and the apoptosis-inducing effects of arsenic trioxide results in a clear therapeutic benefit for t(8;21) AML.