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Cancer Cell. 2018 Aug 13;34(2):286-297.e10. doi: 10.1016/j.ccell.2018.06.014. Epub 2018 Jul 26.

Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma.

Author information

1
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido 060-8638, Japan.
2
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
3
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Division of Pre-Clinical Innovation, NCATS, NIH, Bethesda, MD 20892, USA.
4
Biometric Research Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
5
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Division of Bioinformatics and Biostatistics, NCTR/FDA, Jefferson, AR 72079, USA.
6
Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA.
7
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
8
Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido 060-8638, Japan.
9
Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
10
Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA.
11
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: tawald@helix.nih.gov.
12
Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: lstaudt@mail.nih.gov.

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.

KEYWORDS:

ATLL; BATF3; BET inhibitor; HBZ; functional genomics

PMID:
30057145
DOI:
10.1016/j.ccell.2018.06.014
[Indexed for MEDLINE]

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