Genomic characterization of resistant and relapsed adult B-cell acute lymphoblastic leukemia.

Here, we implemented WGS to characterize the genomic landscape of B-cell acute lymphoblastic leukemia (B-ALL), with emphasis on resistant/relapsed (R/R) cases. The study group contained 64 adult patients with B-ALL diagnosed and treated between 2008 and 2023, including 29 R/R cases. WGS-based mutation analysis was conducted in reference to the immunological and cytogenetic subtypes of the disease and response to therapy. In total, we identified 2,237 variants across 1,267 genes, including 248 pathogenic and 126 likely pathogenic genetic lesions. The numerous associations between the mutation profiles and B-ALL subtypes were found. Notably, 517 genes harbored variants exclusive to the R/R group. Mutated genes were significantly enriched in pathways related to DNA repair (e.g., BRCA2, FANCM), kinase signaling (JAK2, NF1), and chromatin remodeling (CREBBP, BARD1), as well as the gene ontology term “regulation of phosphorylation” (GO:0042325). The results of our study suggest an association between the presence of mutations in genes encoding proteins involved in phosphorylation processes and the R/R B-ALL. Furthermore, R/R patients also exhibited an increased mutational burden compared to those who responded to therapy. This highlights the need for precise evaluation of the nature of molecular changes in individual patients to determine the risk of therapy failure.