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

Masao Nakagawa; Arthur L Shaffer 3rd; Michele Ceribelli; Meili Zhang; George Wright; Da Wei Huang; Wenming Xiao; John Powell; Michael N Petrus; Yibin Yang; James D Phelan; Holger Kohlhammer; Sigrid P Dubois; Hee Min Yoo; Emmanuel Bachy; Daniel E Webster; Yandan Yang; Weihong Xu; Xin Yu; Hong Zhao; Bonita R Bryant; Joji Shimono; Takashi Ishio; Michiyuki Maeda; Patrick L Green; Thomas A Waldmann; Louis M Staudt

doi:10.1016/j.ccell.2018.06.014

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

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

Authors

Masao Nakagawa¹, Arthur L Shaffer 3rd², Michele Ceribelli³, Meili Zhang², George Wright⁴, Da Wei Huang², Wenming Xiao⁵, John Powell⁶, Michael N Petrus², Yibin Yang⁷, James D Phelan², Holger Kohlhammer², Sigrid P Dubois², Hee Min Yoo², Emmanuel Bachy², Daniel E Webster², Yandan Yang², Weihong Xu², Xin Yu², Hong Zhao², Bonita R Bryant², Joji Shimono⁸, Takashi Ishio⁸, Michiyuki Maeda⁹, Patrick L Green¹⁰, Thomas A Waldmann¹¹, Louis M Staudt¹²

Affiliations

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: [email protected].
¹² Lymphoid Malignancies Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address: [email protected].

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.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic-Leucine Zipper Transcription Factors / genetics*
Basic-Leucine Zipper Transcription Factors / physiology
Cell Line, Tumor
Gene Regulatory Networks*
Genes, myc
Human T-lymphotropic virus 1 / physiology*
Humans
Interferon Regulatory Factors / genetics*
Leukemia-Lymphoma, Adult T-Cell / genetics*
Mice
Proteins / antagonists & inhibitors
Retroviridae Proteins / physiology

Substances

BATF protein, human
Basic-Leucine Zipper Transcription Factors
HBZ protein, human T-cell leukemia virus type I
Interferon Regulatory Factors
Proteins
Retroviridae Proteins
bromodomain and extra-terminal domain protein, human
interferon regulatory factor-4

Abstract

Publication types

MeSH terms

Substances

Grants and funding