T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia.
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Roessner Philipp M, Seufert Isabelle, Chapaprieta Vicente, Jayabalan Ruparoshni, Briesch Hannah, Massoni-Badosa Ramon, Boskovic Pavle, Benckendorff Julian, Roider Tobias, Arseni Lavinia, Coelho Mariana, Chakraborty Supriya, Vaca Alicia M, Sivina Mariela, Muckenhuber Markus, Rodriguez-Rodriguez Sonia, Bonato Alice, Herbst Sophie A, Zapatka Marc, Sun Clare, Kretzmer Helene, Naake Thomas, Bruch Peter-Martin, Czernilofsky Felix, Ten Hacken Elisa, Schneider Martin, Helm Dominic, Yosifov Deyan Y, Kauer Joseph, Danilov Alexey V, Bewarder Moritz, Heyne Kristina, Schneider Christof, Stilgenbauer Stephan, Wiestner Adrian, Mallm Jan-Philipp, Burger Jan A, Efremov Dimitar G, Lichter Peter, Dietrich Sascha, Martin-Subero José I, Rippe Karsten, Seiffert Martina
Аннотация
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.