T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia
Year: 2024
Type: article
Abstract: ABSTRACT: The T-box transcription factor T-bet is known as a master regulator of the T-cell response but its role in malignant B cells has not been sufficiently explored. Here, we conducted single-cell resolved multi-omics analyses of malignant B cells from patients with chronic lymphocytic leukemia (CLL) and studied a CLL mouse model with a genetic knockout of Tbx21. We found that T-bet acts as a tumor suppressor in malignant B cells by decreasing their proliferation rate. NF-κB activity, induced by inflammatory signals provided by the microenvironment, triggered T-bet expression, which affected promoter-proximal and distal chromatin coaccessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling and negative control of proliferation by T-bet. In line, we showed that T-bet represses cell cycling and is associated with longer overall survival of patients with CLL. Our study uncovered a novel tumor suppressive role of T-bet in malignant B cells via its regulation of inflammatory processes and cell cycling, which has implications for the stratification and therapy of patients with CLL. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in the inflammatory signaling pathways in CLL.
Source: Blood
Authors: Philipp M. Roessner, Isabelle Seufert, Vicente Chapaprieta, Ruparoshni Jayabalan, Hannah Briesch, Ramon Massoni-Badosa, Pavle Boskovic, Julian Benckendorff, Tobias Roider, Lavinia Arseni, Mariana Coelho, Supriya Chakraborty, Alicia M. Vaca, Mariela Sivina, Markus Muckenhuber, Sonia Rodriguez-Rodriguez, Alice Bonato, Sophie A. Herbst, Marc Zapatka, Clare Sun, Helene Kretzmer, Thomas Naake, Peter-Martin Bruch, Felix Czernilofsky, Elisa ten Hacken, Martin Schneider, Dominic Helm, Deyan Y. Yosifov, Joseph Kauer, Alexey V. Danilov, Moritz Bewarder, Kristina Heyne, Christof Schneider, Stephan Stilgenbauer, Adrian Wiestner, Jan-Philipp Mallm, Jan A. Burger, Dimitar G. Efremov, Peter Lichter, Sascha Dietrich, José I. Martin-Subero, Karsten Rippe, Martina Seiffert
Institutions: German Cancer Research Center, Heidelberg University, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona Institute of Science and Technology, Centre for Genomic Regulation, Weill Cornell Medicine, Washington University in St. Louis, Universität Ulm, University Hospital Ulm, University Hospital Heidelberg, International Centre for Genetic Engineering and Biotechnology, The University of Texas MD Anderson Cancer Center, City Of Hope National Medical Center, National Institutes of Health, National Heart, Lung, and Blood Institute, Max Planck Institute for Molecular Genetics, European Molecular Biology Laboratory, European Molecular Biology Laboratory, Düsseldorf University Hospital, Dana-Farber Cancer Institute, City of Hope, Universitätsklinikum des Saarlandes, Saarland University, Institució Catalana de Recerca i Estudis Avançats, Hospital Clínic de Barcelona, Universitat de Barcelona
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4396214017