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Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics
Meyling Cheok, Wenjian Yang, Gianluigi Zaza, Qing Cheng, John C. Panetta, Ching-Hon Pui, James R. Downing, Mary V. Relling, and William E. Evans
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Published February 1, 2005 - More info
J Clin Invest. 2005;115(2):477–477. https://doi.org/10.1172/JCI22477E1.
© 2005 The American Society for Clinical Investigation
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Abstract
The ability of leukemia cells to accumulate methotrexate polyglutamate (MTXPG) is an important determinant of the antileukemic effects of methotrexate (MTX). We measured in vivo MTXPG accumulation in leukemia cells from 101 children with acute lymphoblastic leukemia (ALL) and established that B-lineage ALL with either TEL-AML1 or E2A-PBX1 gene fusion, or T-lineage ALL, accumulates significantly lower MTXPG compared with B-lineage ALL without these genetic abnormalities or compared with hyperdiploid (fewer than 50 chromosomes) ALL. To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays to analyze expression of 32 folate pathway genes in diagnostic leukemia cells from 197 children. This revealed ALL subtype–specific patterns of folate pathway gene expression that were significantly related to MTXPG accumulation. We found significantly lower expression of the reduced folate carrier (SLC19A1, an MTX uptake transporter) in E2A-PBX1 ALL, significantly higher expression of breast cancer resistance protein (ABCG2, an MTX efflux transporter) in TEL-AML1 ALL, and lower expression of FPGS (which catalyzes formation of MTXPG) in T-lineage ALL, consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome these potential causes of treatment failure in childhood ALL.
Authors
Leo Kager, Meyling Cheok, Wenjian Yang, Gianluigi Zaza, Qing Cheng, John C. Panetta, Ching-Hon Pui, James R. Downing, Mary V. Relling, William E. Evans
Original citation: J. Clin. Invest.115:110–117(2004). doi:10.1172/JCI22477
Citation for this erratum: J. Clin. Invest.115:477 (2005). doi:10.1172/JCI22477E1
During preparation of this manuscript for publication, errors were introduced into the abstract and introduction. The second sentence of the abstract incorrectly included the phrase “fewer than.” The sentence should read:
“We measured in vivo MTXPG accumulation in leukemia cells from 101 children with acute lymphoblastic leukemia (ALL) and established that B-lineage ALL with either TEL-AML1 or E2A-PBX1 gene fusion, or T-lineage ALL, accumulates significantly lower MTXPG compared with B-lineage ALL without these genetic abnormalities or compared with hyperdiploid (greater than 50 chromosomes) ALL.”
The third sentence of the introduction also incorrectly stated “fewer than.” This sentence should read:
“Subtypes with a relatively unfavorable prognosis on many treatment protocols include T-lineage ALL (T-ALL) and ALL with rearranged MLL genes or with BCR-ABL gene fusion, whereas ALL with either TEL-AML1 or E2A-PBX1 gene fusions, or hyperdiploid karyotypes (greater than 50 chromosomes), have a relatively good prognosis with most treatment protocols . . .”
We regret these errors.
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