The t(8;21) translocation is one of the most common genetic lesions associated with acute myeloid leukemia (AML). This translocation juxtaposes the majority of the AML1 gene with ETO, resulting in a transcriptional regulator which aberrantly recruits a repressor complex, containing histone deacetylases (HDACs), to AML1 target sequences. The standard of care for AML is currently limited to initiation and consolidation chemotherapy followed by stem cell transplantation. As AML is a vastly heterogenous disease, there is a need to develop more targeted therapeutic approaches, particuarly as many patients are not eligible for high-dose chemotherapy or stem cell transplant due to their age or other factors

Histone deacetylase inhibitors (HDACi) target the activity of HDACs, altering the acetylation of histones and other proteins. Using a mouse model of t(8;21) AML we have demonstrated that  treatment with the HDACi panobinostat (LBH-589) results in a clear survival benefit. The effects that we observe include degradation of the fusion protein, cell cycle arrest and terminal myeloid differentiation.

To analyze gene expression changes associated with these effects, we performed next generation sequencing on t(8;21) tumours harvested from in vivo treated mice and identified the Type I interferon pathway to be one of the most upregulated pathways. Subsequent analysis has identified the IFNa/b receptor to be a critical component of the response to panobinostat. Tumours lacking the IFNa/b receptor still undergo cell cycle arrest but have an attenuated differentiation response resulting in delayed tumor clearance and a loss of therapeutic effiacy.

Here, we show the HDACi panobinostat induces a Type-I IFN-like response that involves the IFNa/b receptor and link activation of this signaling pathway to the differentiation effect seen in tumour cells following treatment.