The transcription factor IRF8 counteracts BCR-ABL to rescue dendritic cell development in chronic myelogenous leukemia.
The transcription factor IRF8 counteracts BCR-ABL to rescue dendritic cell development in chronic myelogenous leukemia.
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DOI：
10.1158/0008-5472.can-13-0802
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发表时间：
2013-11
期刊：
影响因子：
11.2
通讯作者：
Tomoya Watanabe;C. Hotta;S. Koizumi;Kazuho Miyashita;J. Nakabayashi;D. Kurotaki;Go R. Sato;Michio Yamamoto;M. Nakazawa;H. Fujita;R. Sakai;S. Fujisawa;A. Nishiyama;Z. Ikezawa;M. Aihara;Y. Ishigatsubo;T. Tamura
中科院分区：
文献类型：
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作者：
Tomoya Watanabe;C. Hotta;S. Koizumi;Kazuho Miyashita;J. Nakabayashi;D. Kurotaki;Go R. Sato;Michio Yamamoto;M. Nakazawa;H. Fujita;R. Sakai;S. Fujisawa;A. Nishiyama;Z. Ikezawa;M. Aihara;Y. Ishigatsubo;T. Tamura
BCR-ABL酪氨酸激酶抑制剂（TKI）显著改善了慢性粒细胞白血病（CML）的治疗。然而，导致TKI耐药性的几个问题仍然阻碍了这种疾病的完全治愈。IFN调节因子-8（IRF 8）是免疫细胞（包括树突状细胞）的发育和功能所必需的转录因子。IRF 8（-/-）小鼠发生CML样疾病，IRF 8表达在CML患者中下调，表明IRF 8参与CML的发病机制。在这项研究中，通过使用小鼠CML模型，我们表明，BCR-ABL强烈抑制树突状细胞从体内分化的早期阶段，伴随着抑制Irf 8表达的一代。IRF 8的强制表达推翻BCR-ABL（野生型和T315 I突变型），以拯救体外树突状细胞发育，表明抑制IRF 8导致树突状细胞缺陷。基因表达谱分析显示，IRF 8恢复了BCR-ABL失调基因的显著部分的表达，并预测BCR-ABL具有免疫刺激潜力。事实上，IRF 8拯救的表达BCR-ABL的树突状细胞能够比对照树突状细胞更有效地诱导CTL。总而言之，我们的研究结果表明，IRF 8是下一代CML治疗的一个有吸引力的靶点。
BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells. Irf8(-/-) mice develop a CML-like disease and IRF8 expression is downregulated in patients with CML, suggesting that IRF8 is involved in the pathogenesis of CML. In this study, by using a murine CML model, we show that BCR-ABL strongly inhibits a generation of dendritic cells 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 T315I-mutated) to rescue dendritic cell development in vitro, indicating that the suppression of Irf8 causes dendritic cell 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 dendritic cells were capable of inducing CTLs more efficiently than control dendritic cells. Altogether, our findings suggest that IRF8 is an attractive target in next-generation therapies for CML.