Research ArticleCancer

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

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Science Translational Medicine  19 Jun 2019:
Vol. 11, Issue 497, eaav5599
DOI: 10.1126/scitranslmed.aav5599

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Lymphoma’s gain is its loss

Activated B cell (ABC-like) diffuse large B cell lymphoma (DLBCL) can be curable, but therapies are needed for those who relapse or are refractory to current treatments. Jain et al. found that a percentage of ABC-like DLBCL patient tumors had copy gains on part of chromosome 18. The gains increased expression of transcription factor TCF4 (E2-2), which, in turn, activated immunoglobulin μ and MYC. Finding that tumors with this gain were dependent on TCF4 and that TCF4 was regulated by bromodomain protein BRD4, they tested bromodomain inhibition in xenograft models and reported reduced tumor growth and enhanced survival. This work suggests that targeting TCF4 may hold promise against ABC-like DLBCL.

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 μ (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 proteolysis-targeting 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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