| First Author | Ullah MA | Year | 2024 |
| Journal | Front Immunol | Volume | 15 |
| Pages | 1345515 | PubMed ID | 38469292 |
| Mgi Jnum | J:346084 | Mgi Id | MGI:7612930 |
| Doi | 10.3389/fimmu.2024.1345515 | Citation | Ullah MA, et al. (2024) An unappreciated cell survival-independent role for BAFF initiating chronic lymphocytic leukemia. Front Immunol 15:1345515 |
| abstractText | BACKGROUND: Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19(+) CD5(+) B cells but its origin remains debated. Mutated CLL may originate from post-germinal center B cells and unmutated CLL from CD5(+) mature B cell precursors. Irrespective of precursor types, events initiating CLL remain unknown. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation remains unclear. METHODS: We generated novel CLL models lacking BAFF or APRIL. In vivo experiments were conducted to explore the impact of BAFF or APRIL loss on leukemia initiation, progression, and dissemination. Additionally, RNA-seq and quantitative real-time PCR were performed to unveil the transcriptomic signature influenced by BAFF in CLL. The direct role of BAFF in controlling the expression of tumor-promoting genes was further assessed in patient-derived primary CLL cells ex-vivo. RESULTS: Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumor-promoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo. CONCLUSIONS: Our study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output. |
