作者
Philipp M. Roessner,Isabelle Seufert,Vicente Chapaprieta,Ruparoshni Jayabalan,Hannah Briesch,Ramón Massoni-Badosa,Pavle Boskovic,Julian Beckendorff,Tobias Roider,Lavinia Arseni,Mariana de Freitas 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 Yordanov 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. Martín‐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.