作者
Philipp M. Roessner,Isabelle Seufert,Vicente Chapaprieta,Ruparoshni Jayabalan,Hannah Briesch,Ramon Massoni-Badosa,Pavle Boskovic,Julian Beckendorff,Tobias Roider,Lavinia Arseni,Mariana Coelho,Supriya Chakraborty,Alicia 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. Martı́n-Subero,Karsten Rippe,Martina Seiffert
摘要
The T-box transcription factor T-bet is known as a master regulator of T-cell response but its role in malignant B cells is not 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 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 impacted on promoter proximal and distal chromatin co-accessibility and controlled a specific gene signature by mainly suppressing transcription. Gene set enrichment analysis identified a positive regulation of interferon signaling, and a 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 CLL patients. Our study uncovers 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 stratification and therapy of CLL patients. Linking T-bet activity to inflammation explains the good prognostic role of genetic alterations in inflammatory signaling pathways in CLL.