Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia

Marianne G. Rots, Rob Pieters, Godefridus J. Peters, Paul Noordhuis, Christina H. Van Zantwijk, Gertjan J.L. Kaspers, Karel Hählen, Ursula Creutzig, Anjo J.P. Veerman, Gerrit Jansen

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126 Citations (Scopus)

Abstract

Inefficient polyglutamylation is a mechanism of resistance to methotrexate (MTX) in childhood T-lineage acute lymphoblastic leukemia (T- ALL) and in acute myeloid leukemia (AML) in comparison with childhood c/preB- ALL. We analyzed the profile of MTX polyglutamylation in childhood c/preB- ALL, T-ALL, and AML (n = 45, 15, and 14, respectively), the activity of the MTX-polyglutamate synthesizing enzyme folylpolyglutamate synthetase (FPGS) (n = 39, 11, and 19, respectively) and of the MTX-polyglutamate breakdown enzyme folylpolyglutamate hydrolase (FPGH) (n = 98, 25, and 34, respectively). MTX- Glu(4-6) accumulation after 24 hours exposure to 1 μmol/L [3H]-MTX in vitro was lower in T-ALL (threefold) and AML (fourfold) compared with c/preB-ALL (P ≤ .001). The FPGS activity was twofold lower in T-ALL and AML than in c/preB-ALL samples (P<.01). FPGH activity was not different between c/preB- ALL and T-ALL, but threefold higher in AML (P < .001). FPGS, FPGH, and the ratio FPGS/FPGH were correlated with MTX-Glu(4-6) accumulation (r=.49, r=- .34 and r=.61, respectively). Multivariate analysis showed that FPGS, but not FPGH, was an independent contributor for MTX-Glu(1-6) accumulation, but not for MTXGlu(4-6) accumulation. In conclusion, low FPGS activity is associated with low accumulation of MTX-Glu(4-6) in T-ALL and AML. For the group of AML as compared with the group of ALL, a high FPGH activity can play an additional role.

Original languageEnglish
Pages (from-to)1677-1683
Number of pages7
JournalBlood
Volume93
Issue number5
DOIs
Publication statusPublished - 1 Mar 1999
Externally publishedYes

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