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

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• 作者：Tomoya Watanabe ; Chie Hotta ; Shin-ichi Koizumi ; Kazuho Miyashita ; Jun Nakabayashi ; Daisuke Kurotaki ; Go R. Sato ; Michio Yamamoto ; Akira Nishiyama ; Michiko Aihara ; Yoshiaki Ishigatsubo ; Tomohiko Tamura
• 刊名：Cytokine
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：63
• 期：3
• 页码：308
• 全文大小：44 K

文摘

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.