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

Autor:	Jain N; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Hartert K; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Tadros S; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Fiskus W; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Havranek O; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Ma MCJ; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Bouska A; Department of Pathology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Heavican T; Department of Pathology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Kumar D; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Deng Q; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Moore D; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA., Pak C; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Liu CL; Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA., Gentles AJ; Department of Radiology, Stanford University, Stanford, CA 94305, USA., Hartmann E; Institute of Pathology, University of Würzburg, Würzburg 97080, Germany.; Comprehensive Cancer Center Mainfranken, Wurzburg 97080, Germany., Kridel R; Princess Margaret Cancer Center, University of Toronto, Toronto, ON M5G 2C4, Canada., Smedby KE; Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm SE-171 76, Sweden., Juliusson G; Department of Laboratory Medicine, Stem Cell Center, Lund University, Lund SE-221 00, Sweden., Rosenquist R; Department of Molecular Medicine and Surgery, Karolinska Universitetssjukhuset, Stockholm SE-171 76, Sweden., Gascoyne RD; Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada., Rosenwald A; Institute of Pathology, University of Würzburg, Würzburg 97080, Germany.; Comprehensive Cancer Center Mainfranken, Wurzburg 97080, Germany., Giancotti F; Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Neelapu SS; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Westin J; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Vose JM; Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA., Lunning MA; Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA., Greiner T; Department of Pathology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Rodig S; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Iqbal J; Department of Pathology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA., Alizadeh AA; Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305, USA., Davis RE; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Bhalla K; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Green MR; Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mgreen5@mdanderson.org.; Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2019 Jun 19; Vol. 11 (497).
DOI:	10.1126/scitranslmed.aav5599
Abstrakt:	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. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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