The transcription factor IRF8 counteracts BCR-ABL to rescue dendritic cell development in chronic myelogenous leukemia

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

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6642-6653
Number of pages12
JournalCancer Research
Volume73
Issue number22
DOIs
Publication statusPublished - Nov 15 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'The transcription factor IRF8 counteracts BCR-ABL to rescue dendritic cell development in chronic myelogenous leukemia'. Together they form a unique fingerprint.

Cite this