Genetic Determinants of Treatment-Related Bone Toxicity in Pediatric Acute Lymphoblastic Leukemia.

Osteonecrosis and fractures are serious corticosteroid-induced bone toxicities in children treated for acute lymphoblastic leukemia, yet their genetic determinants remain incompletely defined. In this study, we aimed to identify novel genetic contributors to bone toxicity and to evaluate the robustness of both newly identified and previously established risk genotypes in more recent Dana-Farber Cancer Institute treatment protocols. Whole-exome sequencing was first performed in a discovery cohort to identify genetic variants associated with osteonecrosis. A novel association with a variant in the PGAP2 gene was identified and subsequently confirmed in an independent replication cohort, with effects of patient- and disease-related characteristics observed in both cohorts. Next, previously reported candidate gene-derived associations, together with this newly identified variant, were assessed in a more recent cohort to examine their relevance in contemporary treatment protocols. Variants in BCL2L11 and the ACP1-SH3YL1 locus were associated with bone fractures, with a strong synergistic effect and significant modulation by protocol-specific factors, particularly corticosteroid exposure and asparaginase formulation. The PGAP2 variant was associated with the combined osteonecrosis-fracture phenotype. Transcriptomic analyses revealed isoform-specific expression shifts in PGAP2 in patients with osteotoxicity, supporting a potential functional role for altered splicing or gene regulation. Together, our results provide insight into the pharmacogenomic architecture of osteotoxicity in ALL, demonstrating that PGAP2, BCL2L11, and ACP1-SH3YL1 variants remain clinically relevant predictors of bone toxicity across evolving treatment protocols. However, their clinical manifestations appear to be context-dependent, underscoring the importance of integrating genetic susceptibility with pharmacologic exposures and supporting further investigation of the underlying molecular mechanisms.