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Differences in constitutive and post-methotrexate folylpolyglutamate
synthetase activity in B-lineage and T-lineage leukemia
JC Barredo, TW Synold, J Laver, MV Relling, CH Pui, DG Priest and WE Evans
Department of Pediatrics, Medical University of South Carolina, Charleston
29425.
Folylpolyglutamate synthetase (FPGS) is responsible for the metabolism of
natural folates and a broad range of folate antagonists to polyglutamate
derivatives. Recent studies indicated increased accumulation of
methotrexate (MTX) polyglutamates (MTX-PG) in blast cells as a predictor of
favorable treatment outcome in childhood acute lymphoblastic leukemia
(ALL). We determined the expression of FPGS activity in blasts from
children with ALL at diagnosis and after treatment with MTX as a single
agent, before conventional remission induction therapy. The levels of
enzyme activity in ALL blasts at diagnosis (median of 689 pmol/h/mg
protein) were significantly higher (P = .003) than those found in acute
nonlymphoblastic leukemia (ANLL) blasts (median of 181 pmol/h/mg protein).
Comparable lineage differences in normal lymphoid versus nonlymphoid cells
suggest a lineage-specific control of FPGS expression, FPGS activity
increased in ALL blasts after in vivo exposure to MTX. The median increase
in FPGS activity was significantly higher (P = .003) in B-lineage ALL
(188%) than in T-lineage ALL (37%). Likewise, the percentage of
intracellular long chain MTX-PG (Glu3-6) was significantly higher (P = .02)
in B- lineage ALL (92%) than in T-lineage ALL (65%), consistent with higher
FPGS activity in B-lineage blasts. This finding could explain, at least in
part, the superior outcome in children with B-lineage ALL treated with
antimetabolite therapy.
Volume 84,
Issue 2,
pp. 564-569,
07/15/1994
Copyright © 1994 by The American Society of Hematology
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