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. Gascoyne; Andreas 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

doi:10.1126/scitranslmed.aav5599

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 journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Article number	eaav5599
Journal	Science translational medicine
Volume	11
Issue number	497
DOIs	https://doi.org/10.1126/scitranslmed.aav5599
State	Published - 2019

ASJC Scopus subject areas

General Medicine

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Research Animal Support Facility
Small Animal Imaging Facility
Cytogenetics and Cell Authentication Core

Access to Document

10.1126/scitranslmed.aav5599

Cite this

Jain, N., Hartert, K., Tadros, S., Fiskus, W., Havranek, O., Ma, M. C. J., Bouska, A., Heavican, T., Kumar, D., Deng, Q., Moore, D., Pak, C., Liu, C. L., Gentles, A. J., Hartmann, E., Kridel, R., Smedby, K. E., Juliusson, G., Rosenquist, R., ... 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), Article eaav5599. https://doi.org/10.1126/scitranslmed.aav5599

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

@article{2250f9ed79494b4188f35737d82974bf,

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

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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2019 The Authors, some rights reserved.",

year = "2019",

doi = "10.1126/scitranslmed.aav5599",

language = "English (US)",

volume = "11",

journal = "Science translational medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "497",

}

TY - JOUR

T1 - Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma

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

Y1 - 2019

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85068372931&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068372931&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aav5599

DO - 10.1126/scitranslmed.aav5599

M3 - Article

C2 - 31217338

AN - SCOPUS:85068372931

SN - 1946-6234

VL - 11

JO - Science translational medicine

JF - Science translational medicine

IS - 497

M1 - eaav5599

ER -

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this