275 : The transcription factor IRF8 overrides BCR-ABL to rescue dendritic cell development in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is caused by the BCR-ABL oncoprotein. BCR-ABL tyrosine kinase inhibitors (TKIs) have dramatically improved therapy for CML. However, several problems leading to TKI resistance still impede a complete cure of this disease. In addition, while CML is highly sensitive to tumor immunity, it has been shown that TKIs may suppress functions of T cells and dendritic cells (DCs). Therefore, new therapies for CML are required. Interferon Regulatory Factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells including DCs. Irf8−/− mice develop a CML-like disease and IRF8 expression is downregulated in CML patients, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by employing a murine CML model, we show that BCR-ABL strongly inhibits generation of DCs from an early stage of their differentiation in vivo, concomitant with suppression of Irf8 expression. Forced expression of IRF8 overrode BCR-ABL (both wild-type and TKI-resistant T315I) to rescue DC development in vitro, indicating that the suppression of Irf8 is a cause for the DC deficiency. Gene expression profiling revealed that IRF8 restored the expression of a significant portion of BCR-ABL-dysregulated genes, and predicted that BCR-ABL has immune-stimulatory potential. Indeed, IRF8-rescued, BCR-ABL-expressing DCs were capable of inducing cytotoxic T cells more efficiently than control DCs. Thus, IRF8 appears to “convert” BCR-ABL from a DC suppressor to a DC activator. Taken together, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML.