T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia.
Philipp M RoessnerIsabelle SeufertVicente ChapaprietaRuparoshni JayabalanHannah BrieschRamon Massoni-BadosaPavle BoskovicJulian BeckendorffTobias RoiderLavinia ArseniMariana CoelhoSupriya ChakrabortyAlicia VacaMariela SivinaMarkus MuckenhuberSonia Rodriguez-RodriguezAlice BonatoSophie A HerbstMarc ZapatkaClare SunHelene KretzmerThomas NaakePeter-Martin BruchFelix CzernilofskyElisa Ten HackenMartin SchneiderDominic HelmDeyan Yordanov YosifovJoseph KauerAlexey V DanilovMoritz BewarderKristina HeyneChristof SchneiderStephan StilgenbauerAdrian WiestnerJan-Philipp MallmJan A BurgerDimitar G EfremovPeter LichterSascha DietrichJosé Ignacio Martín-SuberoKarsten RippeMartina SeiffertPublished in: Blood (2024)
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.
Keyphrases
- chronic lymphocytic leukemia
- signaling pathway
- transcription factor
- single cell
- end stage renal disease
- oxidative stress
- genome wide
- chronic kidney disease
- mouse model
- newly diagnosed
- ejection fraction
- gene expression
- poor prognosis
- rna seq
- dna methylation
- prognostic factors
- pi k akt
- stem cells
- dna damage
- genome wide identification
- peritoneal dialysis
- epithelial mesenchymal transition
- long non coding rna
- mesenchymal stem cells
- patient reported outcomes
- high throughput
- endoplasmic reticulum stress
- toll like receptor
- nuclear factor