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

Neeraj Jain, Keenan Hartert, Saber Tadros, Warren Fiskus, Ondrej Havranek, Man Chun John Ma, Alyssa Bouska, Tayla Heavican, Dhiraj Kumar, Qing Deng, Dalia Moore, Christine Pak, Chih Long Liu, Andrew J. Gentles, Elena Hartmann, Robert Kridel, Karin Ekstrom Smedby, Gunnar Juliusson, Richard Rosenquist, Randy D. GascoyneAndreas Rosenwald, Filippo Giancotti, Sattva S. Neelapu, Jason Westin, Julie M. Vose, Matthew A. Lunning, Timothy Greiner, Scott Rodig, Javeed Iqbal, Ash A. Alizadeh, R. Eric Davis, Kapil Bhalla, Michael R. Green

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Article numbereaav5599
JournalScience translational medicine
Volume11
Issue number497
DOIs
StatePublished - Jan 1 2019

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Lymphoma, Large B-Cell, Diffuse
Immunoglobulins
Cell Line
Genes
DNA
Gene Expression Profiling
Heterografts
Neoplasms
B-Lymphocytes
Transcription Factors
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jain, N., Hartert, K., Tadros, S., Fiskus, W., Havranek, O., Ma, M. C. J., ... Green, M. R. (2019). Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma. Science translational medicine, 11(497), [eaav5599]. https://doi.org/10.1126/scitranslmed.aav5599

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; Deng, Qing; Moore, Dalia; Pak, Christine; Liu, Chih Long; Gentles, Andrew J.; Hartmann, Elena; Kridel, Robert; Smedby, Karin Ekstrom; Juliusson, Gunnar; Rosenquist, Richard; Gascoyne, Randy D.; Rosenwald, Andreas; Giancotti, Filippo; Neelapu, Sattva S.; Westin, Jason; Vose, Julie M.; Lunning, Matthew A.; Greiner, Timothy; Rodig, Scott; Iqbal, Javeed; Alizadeh, Ash A.; Davis, R. Eric; Bhalla, Kapil; Green, Michael R.

In: Science translational medicine, Vol. 11, No. 497, eaav5599, 01.01.2019.

Research output: Contribution to journalArticle

Jain, N, Hartert, K, Tadros, S, Fiskus, W, Havranek, O, Ma, MCJ, Bouska, A, Heavican, T, Kumar, D, Deng, Q, Moore, D, Pak, C, Liu, CL, Gentles, AJ, Hartmann, E, Kridel, R, Smedby, KE, Juliusson, G, Rosenquist, R, Gascoyne, RD, Rosenwald, A, Giancotti, F, Neelapu, SS, Westin, J, Vose, JM, Lunning, MA, Greiner, T, Rodig, S, Iqbal, J, Alizadeh, AA, Davis, RE, Bhalla, K & Green, MR 2019, 'Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma', Science translational medicine, vol. 11, no. 497, eaav5599. https://doi.org/10.1126/scitranslmed.aav5599
Jain, Neeraj ; Hartert, Keenan ; Tadros, Saber ; Fiskus, Warren ; Havranek, Ondrej ; Ma, Man Chun John ; Bouska, Alyssa ; Heavican, Tayla ; Kumar, Dhiraj ; Deng, Qing ; Moore, Dalia ; Pak, Christine ; Liu, Chih Long ; Gentles, Andrew J. ; Hartmann, Elena ; Kridel, Robert ; Smedby, Karin Ekstrom ; Juliusson, Gunnar ; Rosenquist, Richard ; Gascoyne, Randy D. ; Rosenwald, Andreas ; Giancotti, Filippo ; Neelapu, Sattva S. ; Westin, Jason ; Vose, Julie M. ; Lunning, Matthew A. ; Greiner, Timothy ; Rodig, Scott ; Iqbal, Javeed ; Alizadeh, Ash A. ; Davis, R. Eric ; Bhalla, Kapil ; Green, Michael R. / Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma. In: Science translational medicine. 2019 ; Vol. 11, No. 497.
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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 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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AU - Jain, Neeraj

AU - Hartert, Keenan

AU - Tadros, Saber

AU - Fiskus, Warren

AU - Havranek, Ondrej

AU - Ma, Man Chun John

AU - Bouska, Alyssa

AU - Heavican, Tayla

AU - Kumar, Dhiraj

AU - Deng, Qing

AU - Moore, Dalia

AU - Pak, Christine

AU - Liu, Chih Long

AU - Gentles, Andrew J.

AU - Hartmann, Elena

AU - Kridel, Robert

AU - Smedby, Karin Ekstrom

AU - Juliusson, Gunnar

AU - Rosenquist, Richard

AU - Gascoyne, Randy D.

AU - Rosenwald, Andreas

AU - Giancotti, Filippo

AU - Neelapu, Sattva S.

AU - Westin, Jason

AU - Vose, Julie M.

AU - Lunning, Matthew A.

AU - Greiner, Timothy

AU - Rodig, Scott

AU - Iqbal, Javeed

AU - Alizadeh, Ash A.

AU - Davis, R. Eric

AU - Bhalla, Kapil

AU - Green, Michael R.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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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