The transcription factor IRF8 counteracts BCR-ABL to rescue dendritic cell development in chronic myelogenous leukemia.
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' Affiliations: Departments of Immunology, Environmental Immuno-Dermatology, Internal Medicine and Clinical Immunology, and Experimental Animal Science, Yokohama City University Graduate School of Medicine; and Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan.
Tomoya
T
Watanabe
Chie
C
Hotta
Shin-ichi
S
Koizumi
Kazuho
K
Miyashita
Jun
J
Nakabayashi
Daisuke
D
Kurotaki
Go R
GR
Sato
Michio
M
Yamamoto
Masatoshi
M
Nakazawa
Hiroyuki
H
Fujita
Rika
R
Sakai
Shin
S
Fujisawa
Akira
A
Nishiyama
Zenro
Z
Ikezawa
Michiko
M
Aihara
Yoshiaki
Y
Ishigatsubo
Tomohiko
T
Tamura
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics*; D050835:Interferon Regulatory Factors / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D000099185:Interferon Regulatory Factor-8
D016044:Fusion Proteins, bcr-abl; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8