Expression associated polymorphisms and 6-mercaptopurine hematologic toxicity in pediatric acute lymphoblastic leukemia patients

Aim 6-mercaptopurine (6-MP) is a key agent in chemotherapy of childhood acute lymphoblastic leukemia (ALL). Although variants in TPMT and NUDT15 are used to guide dosing, they explain only part of the variability in 6-MP toxicity. Our study aims to identify novel genetic determinants of 6-MP tolerance through expression quantitative trait loci (eQTL) analysis.Materials and methods We used transcriptomic data from patients treated according to Dana-Farber Cancer Institute protocols to identify novel variants that may contribute to interindividual variability in 6-MP tolerance. We identified 17 white blood cells specific eQTLs in genes showing at least four-fold higher expression in patients with severe neutropenia. Association analyses of these variants with 6-MP dose intensity and neutropenia frequency were subsequently performed in 280 ALL patients. Results In these exploratory analyses, homozygotes for minor allele of the rs2012694 variant in the L1TD1 gene was associated with increased neutropenia and reduced 6-MP dose intensity. Conversely, three variants in the CPE gene, rs12509669, rs3775317, and rs35411578, demonstrated protective effect against neutropenia and improved 6-MP tolerance.Conclusion These findings highlight CPE and L1TD1 as candidate loci influencing 6-MP tolerance and provide new insights for the personalization of 6-MP therapy in children with ALL.