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Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma

Jain, Neeraj ; Hartert, Keenan ; Tadros, Saber ; Fiskus, Warren ; Havranek, Ondrej ; Ma, Man Chun John ; Bouska, Alyssa ; Heavican, Tayla ; Kumar, Dhiraj and Deng, Qing , et al. (2019) In Science Translational Medicine 11(497).
Abstract

The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin m (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative... (More)

The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin m (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysistargeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

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Contribution to journal
publication status
published
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Science Translational Medicine
volume
11
issue
497
article number
eaav5599
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85068372931
  • pmid:31217338
ISSN
1946-6234
DOI
10.1126/scitranslmed.aav5599
language
English
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yes
id
6b40473f-c0f2-47e2-b850-50026304b1f2
date added to LUP
2019-07-22 11:59:13
date last changed
2020-02-12 10:12:02
@article{6b40473f-c0f2-47e2-b850-50026304b1f2,
  abstract     = {<p>The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin m (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysistargeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.</p>},
  author       = {Jain, Neeraj and Hartert, Keenan and Tadros, Saber and Fiskus, Warren and Havranek, Ondrej and Ma, Man Chun John and Bouska, Alyssa and Heavican, Tayla and Kumar, Dhiraj and Deng, Qing and Moore, Dalia and Pak, Christine and Liu, Chih Long and Gentles, Andrew J. and Hartmann, Elena and Kridel, Robert and Smedby, Karin Ekstrom and Juliusson, Gunnar and Rosenquist, Richard and Gascoyne, Randy D. and Rosenwald, Andreas and Giancotti, Filippo and Neelapu, Sattva S. and Westin, Jason and Vose, Julie M. and Lunning, Matthew A. and Greiner, Timothy and Rodig, Scott and Iqbal, Javeed and Alizadeh, Ash A. and Davis, R. Eric and Bhalla, Kapil and Green, Michael R.},
  issn         = {1946-6234},
  language     = {eng},
  month        = {06},
  number       = {497},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma},
  url          = {http://dx.doi.org/10.1126/scitranslmed.aav5599},
  doi          = {10.1126/scitranslmed.aav5599},
  volume       = {11},
  year         = {2019},
}