Nov, 2013
The Transcription Factor IRF8 Counteracts BCR-ABL to Rescue Dendritic Cell Development in Chronic Myelogenous Leukemia
CANCER RESEARCH
- Volume
- 73
- Number
- 22
- First page
- 6642
- Last page
- 6653
- Language
- English
- Publishing type
- Research paper (scientific journal)
- DOI
- 10.1158/0008-5472.CAN-13-0802
- Publisher
- 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.
- Link information
- ID information
-
- DOI : 10.1158/0008-5472.CAN-13-0802
- ISSN : 0008-5472
- eISSN : 1538-7445
- Pubmed ID : 24242069
- Web of Science ID : WOS:000327321700011