Targetable genetic alterations of <i>TCF4</i> ( <i>E2-2</i> ) 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 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 <i>TCF4</i> (<i>E2-2</i>) transcription factor gene was the target of these alterations. Overexpression of <i>TCF4</i> in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (<i>IGHM</i>) and <i>MYC</i> 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 <i>TCF4</i> DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the <i>TCF4</i> 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.