Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics
| Autor: | William E. Evans, Qing Cheng, John C. Panetta, Ching-Hon Pui, Leo Kager, Wenjian Yang, James R. Downing, Mary V. Relling, Meyling Cheok, Gianluigi Zaza |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Abcg2
methotrexate polyglutamate acute lymphoblastic leukemia Article Fusion gene Leukocyte Count Folic Acid hemic and lymphatic diseases Gene expression medicine Cluster Analysis Humans Lymphocytes RNA Messenger Regulation of gene expression biology Gene Expression Profiling Transporter DNA Thymidylate Synthase General Medicine Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Gene Expression Regulation Neoplastic Gene expression profiling Leukemia Methotrexate oligonucleotide microarrays Polyglutamic Acid Immunology Cancer research biology.protein medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 115:110-117 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci22477 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|