Author:
Jain Neeraj,Hartert Keenan,Tadros Saber,Fiskus Warren,Havranek Ondrej,John Ma Man-Chun,Bouska Alyssa,Heavican Tayla,Kumar Dhiraj,Deng Qing,Moore Dalia,Pak Christine,Liu Chih Long,Gentles Andrew,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,Lunning Matthew,Greiner Timothy,Rodig Scott,Iqbal Javeed,Alizadeh Ash,Davis R. Eric,Bhalla Kapil,Green Michael R.
Abstract
ABSTRACTThe activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by the chronic activation of signaling initiated by immunoglobulin-μ (IgM). By analyzing DNA copy profiles of 1,000 DLBCLs, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. We show that these alterations target the TCF4 (E2-2) transcription factor, and that over-expression of TCF4 leads to its occupancy on immunoglobulin gene enhancers and increased expression of IgM at the transcript and protein level. The TCF4 gene is one of the top BRD4-regulated genes in DLBCL. Using a BET proteolysis-targeting chimera (PROTAC) we show that TCF4 and IgM expression can be extinguished, and ABC-like DLBCL cells can be killed in vitro and in vivo. This highlights a novel genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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