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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1643-1650
Reduced Folate Carrier Expression in Acute Lymphoblastic Leukemia: A
Mechanism for Ploidy but not Lineage Differences in Methotrexate
Accumulation
Vladimir M. Belkov,
Eugene Y. Krynetski,
John D. Schuetz,
Yuri Yanishevski,
Eric Masson,
Susan Mathew,
Susana Raimondi,
Ching-Hon Pui,
Mary V. Relling, and
William E. Evans
From the St Jude Children's Research Hospital, Memphis, TN; and the
University of Tennessee, Memphis, TN.
Methotrexate (MTX) is one of the most active and widely used agents
for the treatment of acute lymphoblastic leukemia (ALL). To elucidate
the mechanism for higher accumulation of MTX polyglutamates (MTX-PG) in
hyperdiploid ALL and lower accumulation in T-lineage ALL, expression of
the reduced folate carrier (RFC) was assessed by reverse
transcription-polymerase chain reaction in ALL blasts isolated from newly diagnosed patients. RFC expression exhibited a
60-fold range among 29 children, with significantly higher expression in hyperdiploid B-lineage ALL (median, 11.3) compared with
nonhyperdiploid ALL (median, 2.1; P < .0006), but no
significant difference between nonhyperdiploid B-lineage and T-lineage
ALL. Furthermore, mRNA levels of RFC (mapped by FISH to chromosome 21)
were significantly related to chromosome 21 copy number (P = .0013), with the highest expression in hyperdiploid ALL blasts with 4 copies of chromosome 21. To assess the functional significance of gene
copy number, MTX-PG accumulation was compared in ALL blasts isolated
from 121 patients treated with either low-dose MTX (LDMTX; n = 60) or
high-dose MTX (HDMTX; n = 61). After LDMTX, MTX-PG accumulation was
highest in hyperdiploid B-lineage ALL with 4 copies of chromosome 21 (P = .011), but MTX-PG accumulation was not significantly
related to chromosome 21 copy number after HDMTX (P = .24).
These data show higher RFC expression as a mechanism for greater MTX
accumulation in hyperdiploid B-lineage ALL and indicate that lineage
differences in MTX-PG accumulation are not due to lower RFC expression
in T-lineage ALL.
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