TY - JOUR
T1 - DNA polymerase gamma variants and hepatotoxicity during maintenance therapy of childhood acute lymphoblastic leukemia
T2 - is there a causal relationship?
AU - Harju, Tekla
AU - Hurme-Niiranen, Anri
AU - Suo-Palosaari, Maria
AU - Nygaard Nielsen, Stine
AU - Hinttala, Reetta
AU - Schmiegelow, Kjeld
AU - Uusimaa, Johanna
AU - Harila, Arja
AU - Niinimäki, Riitta
N1 - © 2023. The Author(s).
PY - 2023/9
Y1 - 2023/9
N2 - Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.
AB - Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.
KW - Chemical and Drug Induced Liver Injury/genetics
KW - DNA Polymerase gamma
KW - Humans
KW - Mercaptopurine/adverse effects
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Valproic Acid/adverse effects
UR - http://www.scopus.com/inward/record.url?scp=85158075843&partnerID=8YFLogxK
U2 - 10.1038/s41397-023-00303-0
DO - 10.1038/s41397-023-00303-0
M3 - Journal article
C2 - 37138020
SN - 1470-269X
VL - 23
SP - 105
EP - 111
JO - The pharmacogenomics journal
JF - The pharmacogenomics journal
IS - 5
ER -