Milosevic, Goran (55608514200)Goran (55608514200)MilosevicKotur, Nikola (54961068500)Nikola (54961068500)KoturLazic, Jelena (7004184322)Jelena (7004184322)LazicKrstovski, Nada (24724852600)Nada (24724852600)KrstovskiStankovic, Biljana (35785023700)Biljana (35785023700)StankovicZukic, Branka (26030757000)Branka (26030757000)ZukicJanic, Dragana (15729368500)Dragana (15729368500)JanicJurisic, Vladimir (6603015144)Vladimir (6603015144)JurisicPavlovic, Sonja (7006514877)Sonja (7006514877)PavlovicDokmanovic, Lidija (15729287100)Lidija (15729287100)Dokmanovic2025-07-022025-07-022019https://www.scopus.com/inward/record.uri?eid=2-s2.0-85074967588&partnerID=40&md5=942e7a2281e368026ec286232baa2a03https://remedy.med.bg.ac.rs/handle/123456789/12818Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680,-675,-556,-464,-317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants. © 2019 Zerbinis Publications. All rights reserved.6-mercaptopurine myelotoxicityAcute lymphoblastic leukemiaDHFRMTHFRSLC19A1TYMS