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T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia.
- Source :
-
Blood [Blood] 2024 Aug 01; Vol. 144 (5), pp. 510-524. - Publication Year :
- 2024
-
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.
- Subjects :
- Animals
Humans
Mice
B-Lymphocytes pathology
B-Lymphocytes metabolism
B-Lymphocytes immunology
Mice, Knockout
Gene Expression Regulation, Leukemic
NF-kappa B metabolism
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Leukemia, Lymphocytic, Chronic, B-Cell immunology
Leukemia, Lymphocytic, Chronic, B-Cell metabolism
T-Box Domain Proteins genetics
T-Box Domain Proteins metabolism
Cell Proliferation
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 144
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 38684038
- Full Text :
- https://doi.org/10.1182/blood.2023021990