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

Masao Nakagawa; Arthur L. Shaffer; 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

Masao Nakagawa, Arthur L. Shaffer, 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 ZhaoBonita R. Bryant, Joji Shimono, Takashi Ishio, Michiyuki Maeda, Patrick L. Green, Thomas A. Waldmann, Louis M. Staudt

Research output: Contribution to journal › Article › peer-review

87 Scopus citations

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. Nakagawa et al. show that BATF3 and IRF4 cooperatively drive adult T cell leukemia/lymphoma (ATLL)-specific gene expression and that human lymphotropic virus type I encoded HBZ regulates the expression of BATF3 and its downstream targets. BET inhibitors collapse the transcriptional network and kill ATLL cells.

Original language	English
Pages (from-to)	286-297.e10
Journal	Cancer Cell
Volume	34
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2018.06.014
State	Published - Aug 13 2018

Keywords

ATLL
BATF3
BET inhibitor
HBZ
functional genomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2018.06.014

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Nakagawa, M., Shaffer, A. L., Ceribelli, M., Zhang, M., Wright, G., Huang, D. W., Xiao, W., Powell, J., Petrus, M. N., Yang, Y., Phelan, J. D., Kohlhammer, H., Dubois, S. P., Yoo, H. M., Bachy, E., Webster, D. E., Yang, Y., Xu, W., Yu, X., ... Staudt, L. M. (2018). Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma. Cancer Cell, 34(2), 286-297.e10. https://doi.org/10.1016/j.ccell.2018.06.014

@article{ddc36cb2cc824dcba3f9e1d9abaa85ae,

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

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. Nakagawa et al. show that BATF3 and IRF4 cooperatively drive adult T cell leukemia/lymphoma (ATLL)-specific gene expression and that human lymphotropic virus type I encoded HBZ regulates the expression of BATF3 and its downstream targets. BET inhibitors collapse the transcriptional network and kill ATLL cells.",

keywords = "ATLL, BATF3, BET inhibitor, HBZ, functional genomics",

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

note = "Publisher Copyright: {\textcopyright} 2018",

year = "2018",

month = aug,

day = "13",

doi = "10.1016/j.ccell.2018.06.014",

language = "English",

volume = "34",

pages = "286--297.e10",

journal = "Cancer Cell",

issn = "1535-6108",

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Nakagawa, M, Shaffer, AL, Ceribelli, M, Zhang, M, Wright, G, Huang, DW, Xiao, W, Powell, J, Petrus, MN, Yang, Y, Phelan, JD, Kohlhammer, H, Dubois, SP, Yoo, HM, Bachy, E, Webster, DE, Yang, Y, Xu, W, Yu, X, Zhao, H, Bryant, BR, Shimono, J, Ishio, T, Maeda, M, Green, PL, Waldmann, TA & Staudt, LM 2018, 'Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma', Cancer Cell, vol. 34, no. 2, pp. 286-297.e10. https://doi.org/10.1016/j.ccell.2018.06.014

TY - JOUR

T1 - Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma

AU - Nakagawa, Masao

AU - Shaffer, Arthur L.

AU - Ceribelli, Michele

AU - Zhang, Meili

AU - Wright, George

AU - Huang, Da Wei

AU - Xiao, Wenming

AU - Powell, John

AU - Petrus, Michael N.

AU - Yang, Yibin

AU - Phelan, James D.

AU - Kohlhammer, Holger

AU - Dubois, Sigrid P.

AU - Yoo, Hee Min

AU - Bachy, Emmanuel

AU - Webster, Daniel E.

AU - Yang, Yandan

AU - Xu, Weihong

AU - Yu, Xin

AU - Zhao, Hong

AU - Bryant, Bonita R.

AU - Shimono, Joji

AU - Ishio, Takashi

AU - Maeda, Michiyuki

AU - Green, Patrick L.

AU - Waldmann, Thomas A.

AU - Staudt, Louis M.

PY - 2018/8/13

Y1 - 2018/8/13

N2 - 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. Nakagawa et al. show that BATF3 and IRF4 cooperatively drive adult T cell leukemia/lymphoma (ATLL)-specific gene expression and that human lymphotropic virus type I encoded HBZ regulates the expression of BATF3 and its downstream targets. BET inhibitors collapse the transcriptional network and kill ATLL cells.

AB - 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. Nakagawa et al. show that BATF3 and IRF4 cooperatively drive adult T cell leukemia/lymphoma (ATLL)-specific gene expression and that human lymphotropic virus type I encoded HBZ regulates the expression of BATF3 and its downstream targets. BET inhibitors collapse the transcriptional network and kill ATLL cells.

KW - ATLL

KW - BATF3

KW - BET inhibitor

KW - HBZ

KW - functional genomics

UR - http://www.scopus.com/inward/record.url?scp=85053841082&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.06.014

DO - 10.1016/j.ccell.2018.06.014

M3 - Article

SN - 1535-6108

VL - 34

SP - 286-297.e10

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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