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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1677-1683
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, and
Gerrit Jansen
From the Departments of Pediatric Hematology/Oncology and of Medical
Oncology, University Hospital Vrije Universiteit, Amsterdam; the
Department of Pediatric Hematology/Oncology, Sophia Children's
Hospital, Erasmus University, Rotterdam, the Netherlands; and the
AML-BFM Study Group, Germany.
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-Glu4-6 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-Glu4-6 accumulation
(r = .49, r =  .34 and r = .61,
respectively). Multivariate analysis showed that FPGS, but not FPGH,
was an independent contributor for MTX-Glu1-6 accumulation,
but not for MTX-Glu4-6 accumulation. In conclusion, low
FPGS activity is associated with low accumulation of
MTX-Glu4-6 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.
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