TY - JOUR
T1 - Effect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia
AU - de Jonge, Robert
AU - Hooijberg, Jan Hendrik
AU - van Zelst, Bertrand D
AU - Jansen, Gerrit
AU - Jansen, Gerritz
AU - van Zantwijk, Christina H
AU - van Zantwijk, Christine H
AU - Kaspers, Gertjan J L
AU - Kaspers, Gert Jan L
AU - Peters, Godefridus J
AU - Peters, Frits G J
AU - Ravindranath, Yaddanapudi
AU - Pieters, Rob
AU - Lindemans, Jan
PY - 2005/7/15
Y1 - 2005/7/15
N2 - We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI(50, cont)) or short-term (3 hours; TSI(50, short)) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI(50, cont). In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL.
AB - We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI(50, cont)) or short-term (3 hours; TSI(50, short)) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI(50, cont). In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL.
KW - Antimetabolites, Antineoplastic/pharmacology
KW - Child
KW - Drug Resistance, Neoplasm/genetics
KW - Ferredoxin-NADP Reductase/genetics
KW - Folic Acid/genetics
KW - Genetic Variation
KW - Glycine Hydroxymethyltransferase/genetics
KW - Humans
KW - In Vitro Techniques
KW - Methotrexate/pharmacology
KW - Methylenetetrahydrofolate Reductase (NADPH2)/genetics
KW - Polymorphism, Genetic
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
U2 - https://doi.org/10.1182/blood-2004-12-4941
DO - https://doi.org/10.1182/blood-2004-12-4941
M3 - Article
C2 - 15797993
SN - 0006-4971
VL - 106
SP - 717
EP - 720
JO - Blood
JF - Blood
IS - 2
ER -