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Updated: Oct 29, 2026

Assessment of Chimeric Antigen Receptor T Cell-Associated Toxicities Using an Acute Lymphoblastic Leukemia Patient-Derived Xenograft Mouse Model
Published on: February 10, 2023
Expression associated polymorphisms and 6-mercaptopurine hematologic toxicity in pediatric acute lymphoblastic
Zarina Sabirova1,2, Claire Fuchs2, Amine Meskaoui1
1Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
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.
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