Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics
Leo Kager, … , Mary V. Relling, William E. Evans
Leo Kager, … , Mary V. Relling, William E. Evans
Published January 3, 2005
Citation Information: J Clin Invest. 2005;115(1):110-117. https://doi.org/10.1172/JCI22477.
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Article Oncology

Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics

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

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Figure 3

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Gene expression of FPGS and 3 transporters with known MTX transport capa...
Gene expression of FPGS and 3 transporters with known MTX transport capacity in ALL subtypes. Box plots with medians, quartiles, and ranges excluding outliers (circles) of log mRNA expression are depicted for folylpolyglutamate synthetase (FPGS) (A), reduced folate carrier (RFC, or SLC19A1) (B), multidrug resistance–associated protein 1 (MRP1, or ABCC1) (C), and breast cancer resistance protein (BCRP, or ABCG2) (D). Data from 197 patients were plotted (BHD, n = 42; BNHD, n = 58; E2A-PBX1, n = 21; T-ALL, n = 35; TEL-AML1, n = 41). P values were determined by the Kruskal-Wallis test. The red boxes indicate subtypes in which gene expression was significantly higher, whereas the green boxes indicate subtypes with significantly lower expression of the gene depicted.