KEY TAKEAWAYS
- The study aimed to investigate the role of BAFF and APRIL cytokines in initiating CLL independent of cell survival mechanisms.
- Researchers noticed that targeting BAFF could potentially serve as a dual therapeutic approach in CLL, reducing tumor burden and suppressing transformed CLL cell output.
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.
Md Ashik Ullah and the team aimed to assess the potential of BAFF inhibition as a therapeutic strategy targeting CLL initiation and progression, paving the way for novel treatment approaches in this challenging disease.
Researchers performed an inclusive analysis, generating 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 employed 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.
Researchers revealed 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 solely increased CLL cell numbers in the peritoneal cavity, with no dissemination into the periphery.
Although BAFF binding to BAFF-R was unnecessary for peritoneal CLL cell survival, activating a tumor-promoting gene program potentially linked to CLL initiation and progression was essential. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo.
The study concluded 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.
The study was sponsored by the research grants to FM from the National Health and Medical Research Council (NHMRC). PS is supported by the Swiss National Science Foundation
Source: https://pubmed.ncbi.nlm.nih.gov/38469292/
Ullah MA, Garcillán B, Whitlock E, et al. (2024). “An unappreciated cell survival-independent role for BAFF initiating chronic lymphocytic leukemia.” Front Immunol. 2024 Feb 26;15:1345515. doi: 10.3389/fimmu.2024.1345515. PMID: 38469292; PMCID: PMC10927009.
