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Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma.
- Source :
-
Cancer cell [Cancer Cell] 2018 Aug 13; Vol. 34 (2), pp. 286-297.e10. Date of Electronic Publication: 2018 Jul 26. - Publication Year :
- 2018
-
Abstract
- Adult T cell leukemia/lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). RNAi screening of ATLL lines revealed that their proliferation depends on BATF3 and IRF4, which cooperatively drive ATLL-specific gene expression. HBZ, the only HTLV-I encoded transcription factor that is expressed in all ATLL cases, binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including MYC. Inhibitors of bromodomain-and-extra-terminal-domain (BET) chromatin proteins collapsed the transcriptional network directed by HBZ and BATF3, and were consequently toxic for ATLL cell lines, patient samples, and xenografts. Our study demonstrates that the HTLV-I oncogenic retrovirus exploits a regulatory module that can be attacked therapeutically with BET inhibitors.<br /> (Published by Elsevier Inc.)
- Subjects :
- Animals
Basic-Leucine Zipper Transcription Factors physiology
Cell Line, Tumor
Genes, myc
Humans
Mice
Proteins antagonists & inhibitors
Retroviridae Proteins physiology
Basic-Leucine Zipper Transcription Factors genetics
Gene Regulatory Networks
Human T-lymphotropic virus 1 physiology
Interferon Regulatory Factors genetics
Leukemia-Lymphoma, Adult T-Cell genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 34
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 30057145
- Full Text :
- https://doi.org/10.1016/j.ccell.2018.06.014