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Sci Transl Med. 2019 Jun 19;11(497). pii: eaav5599. doi: 10.1126/scitranslmed.aav5599.

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

Author information

1
Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
3
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Pathology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
5
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
8
Department of Radiology, Stanford University, Stanford, CA 94305, USA.
9
Institute of Pathology, University of Würzburg, Würzburg 97080, Germany.
10
Comprehensive Cancer Center Mainfranken, Wurzburg 97080, Germany.
11
Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5G 2C4, Canada.
12
Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
13
Department of Laboratory Medicine, Stem Cell Center, Lund University, Lund SE-221 00, Sweden.
14
Department of Molecular Medicine and Surgery, Karolinska Universitetssjukhuset, Stockholm SE-171 76, Sweden.
15
Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada.
16
Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
17
Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
18
Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mgreen5@mdanderson.org.
19
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

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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