論文

査読有り
2013年11月

The Transcription Factor IRF8 Counteracts BCR-ABL to Rescue Dendritic Cell Development in Chronic Myelogenous Leukemia

CANCER RESEARCH
  • Tomoya Watanabe
  • ,
  • Chie Hotta
  • ,
  • Shin-ichi Koizumi
  • ,
  • Kazuho Miyashita
  • ,
  • Jun Nakabayashi
  • ,
  • Daisuke Kurotaki
  • ,
  • Go R. Sato
  • ,
  • Michio Yamamoto
  • ,
  • Masatoshi Nakazawa
  • ,
  • Hiroyuki Fujita
  • ,
  • Rika Sakai
  • ,
  • Shin Fujisawa
  • ,
  • Akira Nishiyama
  • ,
  • Zenro Ikezawa
  • ,
  • Michiko Aihara
  • ,
  • Yoshiaki Ishigatsubo
  • ,
  • Tomohiko Tamura

73
22
開始ページ
6642
終了ページ
6653
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/0008-5472.CAN-13-0802
出版者・発行元
AMER ASSOC CANCER RESEARCH

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. (C) 2013 AACR.

Web of Science ® 被引用回数 : 11

リンク情報
DOI
https://doi.org/10.1158/0008-5472.CAN-13-0802
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000327321700011&DestApp=WOS_CPL

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