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Targetable genetic ...
Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma
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- Jain, Neeraj (author)
- University of Texas
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- Hartert, Keenan (author)
- University of Nebraska Medical Center
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- Tadros, Saber (author)
- University of Texas,University of Nebraska Medical Center
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- Fiskus, Warren (author)
- University of Texas
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- Havranek, Ondrej (author)
- University of Texas
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- Ma, Man Chun John (author)
- University of Texas
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- Bouska, Alyssa (author)
- University of Nebraska Medical Center
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- Heavican, Tayla (author)
- University of Nebraska Medical Center
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- Kumar, Dhiraj (author)
- University of Texas
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- Deng, Qing (author)
- University of Texas
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- Moore, Dalia (author)
- University of Nebraska Medical Center
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- Pak, Christine (author)
- Brigham and Women's Hospital / Harvard Medical School,Harvard Medical School
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- Liu, Chih Long (author)
- Stanford University
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- Gentles, Andrew J. (author)
- Stanford University
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- Hartmann, Elena (author)
- Julius Maximilian University of Würzburg
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- Kridel, Robert (author)
- University of Toronto
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- Smedby, Karin Ekstrom (author)
- Karolinska Institutet,Karolinska Institute,Karolinska University Hospital
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- Juliusson, Gunnar (author)
- Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine
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- Rosenquist, Richard (author)
- Karolinska Institutet
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- Gascoyne, Randy D. (author)
- British Columbia Cancer Agency
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- Rosenwald, Andreas (author)
- Julius Maximilian University of Würzburg
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- Giancotti, Filippo (author)
- University of Texas
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- Neelapu, Sattva S. (author)
- University of Texas
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- Westin, Jason (author)
- University of Texas
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- Vose, Julie M. (author)
- University of Nebraska Medical Center
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- Lunning, Matthew A. (author)
- University of Nebraska Medical Center
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- Greiner, Timothy (author)
- University of Nebraska Medical Center
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- Rodig, Scott (author)
- Brigham and Women's Hospital / Harvard Medical School,Harvard Medical School
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- Iqbal, Javeed (author)
- University of Nebraska Medical Center
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- Alizadeh, Ash A. (author)
- Stanford University
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- Davis, R. Eric (author)
- University of Texas
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- Bhalla, Kapil (author)
- University of Texas
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- Green, Michael R. (author)
- University of Texas
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(creator_code:org_t)
- American Association for the Advancement of Science (AAAS), 2019
- 2019
- English.
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:497
- Related links:
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http://dx.doi.org/10...
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https://europepmc.or...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Subject headings
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- The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin m (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 proteolysistargeting 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Jain, Neeraj
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Hartert, Keenan
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Tadros, Saber
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Fiskus, Warren
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Havranek, Ondrej
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Ma, Man Chun Joh ...
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show more...
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Bouska, Alyssa
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Heavican, Tayla
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Kumar, Dhiraj
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Deng, Qing
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Moore, Dalia
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Pak, Christine
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Liu, Chih Long
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Gentles, Andrew ...
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Hartmann, Elena
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Kridel, Robert
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Smedby, Karin Ek ...
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Juliusson, Gunna ...
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Rosenquist, Rich ...
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Gascoyne, Randy ...
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Rosenwald, Andre ...
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Giancotti, Filip ...
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Neelapu, Sattva ...
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Westin, Jason
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Vose, Julie M.
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Lunning, Matthew ...
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Greiner, Timothy
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Rodig, Scott
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Iqbal, Javeed
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Alizadeh, Ash A.
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Davis, R. Eric
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Bhalla, Kapil
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Green, Michael R ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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Science Translat ...
- By the university
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Lund University
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Karolinska Institutet