Identification of germline PAX5 variants in pediatric B-ALL: Establishing murine and hiPSC model systems for profiling

PAX5 is crucial for B cell development, regulating key differentiation factors like CD19 and CD79a. While PAX5 somatic mutations occur in one-third of B-ALL cases, this study highlights the impact of germline variants. Sequencing data from 1,161 childhood cancer patients revealed four known (R38H, P80R, G183R, G183S) and ten novel (e.g., R31W, G183Afs, E259K, G343R, Exon 6 deletion, stop loss) PAX5 variants. Six (R31W, G183Afs, E259K, G343R, Exon 6 deletion, stop loss) demonstrated functional relevance in vitro, particularly affecting CD19 and CD79a. RNA sequencing showed significant differences in gene expression impacting B cell development. While murine models have limitations, an iPSC-based human system using CRISPR-Cas9, which is currently under development, could provide deeper insights into B-ALL initiation. Taken together, our data suggest a higher prevalence of PAX5 germline variants than previously assumed.

Publication History

Article published online:
09 May 2025