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. 2005 Jan;115(1):110-7.
doi: 10.1172/JCI22477.

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

Leo Kager  1 , 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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"VSports最新版本" Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics

Leo Kager et al. J Clin Invest. 2005 Jan.

Abstract (V体育官网入口)

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 VSports手机版. .

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Figures

Figure 1
Figure 1
Box plot of intracellular concentration of total methotrexate polyglutamates (MTXPG2–7) according to ALL subtypes, following in vivo treatment with 1 g/m2 MTX infused over 24 hours. MTXPG accumulation (picomoles per 109 bone marrow ALL cells) is shown for hyperdiploid B-lineage ALL (BHD, n = 19), nonhyperdiploid B-lineage ALL without defined molecular genetic abnormalities (BNHD, n = 39), ALL with E2A-PBX1 fusion (E2A-PBX1, n = 5), T-ALL (n = 14), and ALL with TEL-AML1 fusion (TEL-AML1, n = 24). Medians, quartiles, and ranges excluding outliers (circles) are depicted. P values are from pairwise comparisons using the Wilcoxon rank sum test after adjustment for multiple testing.
Figure 2
Figure 2
Unsupervised hierarchical clustering of 25 candidate gene transcripts based on expression in bone marrow ALL cells from 197 newly diagnosed patients with defined ALL subtypes. Each column represents a gene probe set and each row a patient. ALL subtypes are depicted by different colors: red (BHD, n = 42), blue (BNHD, n = 58), yellow (E2A-PBX1, n = 21), black (T-ALL, n = 35), and green (TEL-AML1, n = 41). The gene cluster highlighted in magenta indicates 7 tightly clustered transcripts. The gene cluster highlighted in purple includes most of the transporters (9 transcripts). Probe set signal values were normalized to the mean across patients, and values for each individual case are represented by a color, with green corresponding to SD (ς) below and red corresponding to SD (ς) above the mean, according to the scale shown.
Figure 3
Figure 3
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.
Figure 4
Figure 4
Correlation in mRNA expression levels in ALL cells between DHFR and TYMS, and between TYMS and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). Data are shown for ALL cells from 197 patients. P values are from Pearson correlation. BHD subtypes (n = 42) are depicted in red, BNHD (n = 58) in blue, E2A-PBX1 (n = 21) in yellow, T-ALL (n = 35) in black, and TEL-AML1 (n = 41) in green.
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References (VSports注册入口)

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