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

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.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 22 Pg. 6642-53 (Nov 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 24242069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR

Chemical References

• Interferon Regulatory Factors
• interferon regulatory factor-8
• Fusion Proteins, bcr-abl

Topics

• Animals
• Cell Differentiation
• Cells, Cultured
• Dendritic Cells (immunology)
• Drug Resistance, Neoplasm (genetics)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics)
• Interferon Regulatory Factors (physiology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics, immunology)
• Lymphocyte Activation (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• T-Lymphocytes, Cytotoxic (immunology)