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T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia

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...

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Main Authors: Rößner, Philipp M. (Author) , Seufert, Isabelle (Author) , Chapaprieta, Vicente (Author) , Jayabalan, Ruparoshni (Author) , Briesch, Hannah (Author) , Massoni-Badosa, Ramon (Author) , Boskovic, Pavle (Author) , Benckendorff, Julian (Author) , Roider, Tobias (Author) , Arseni, Lavinia (Author) , Coelho, Mariana (Author) , Chakraborty, Supriya (Author) , Vaca, Alicia M. (Author) , Sivina, Mariela (Author) , Muckenhuber, Markus (Author) , Rodriguez-Rodriguez, Sonia (Author) , Bonato, Alice (Author) , Herbst, Sophie A. (Author) , Zapatka, Marc (Author) , Sun, Clare (Author) , Kretzmer, Helene (Author) , Naake, Thomas (Author) , Bruch, Peter-Martin (Author) , Czernilofsky, Felix (Author) , ten Hacken, Elisa (Author) , Schneider, Martin (Author) , Helm, Dominic (Author) , Yosifov, Deyan Y. (Author) , Kauer, Joseph (Author) , Danilov, Alexey V. (Author) , Bewarder, Moritz (Author) , Heyne, Kristina (Author) , Schneider, Christof (Author) , Stilgenbauer, Stephan (Author) , Wiestner, Adrian (Author) , Mallm, Jan-Philipp (Author) , Burger, Jan A. (Author) , Efremov, Dimitar G. (Author) , Lichter, Peter (Author) , Dietrich, Sascha (Author) , Martin-Subero, José I. (Author) , Rippe, Karsten (Author) , Seiffert, Martina (Author)
Format: Article (Journal)
Language:English
Published: August 1 2024
In: Blood
Year: 2024, Volume: 144, Issue: 5, Pages: 510-524
ISSN:1528-0020
DOI:10.1182/blood.2023021990
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2023021990
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Author Notes: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

MARC

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520 |a 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. 
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