Faculty, Staff and Student Publications

Language

English

Publication Date

8-1-2024

Journal

Blood

DOI

10.1182/blood.2023021990

PMID

38684038

PMCID

PMC11307267

PubMedCentral® Posted Date

5-2-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Leukemia, Lymphocytic, Chronic, B-Cell, T-Box Domain Proteins, Animals, Humans, Cell Proliferation, Mice, B-Lymphocytes, Mice, Knockout, Gene Expression Regulation, Leukemic, NF-kappa B, T-bet Transcription Factor

Published Open-Access

yes

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