title: 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.affiliation: Hematological Malignancies Program, and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Kager
authors.forename: Meyling
authors.initials: M
authors.lastname: Cheok
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D016000:Cluster Analysis; D004247:DNA / Q000096:biosynthesis; D005492:Folic Acid / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007958:Leukocyte Count; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D004247:DNA; D005492:Folic Acid; D013940:Thymidylate Synthase; D008727:Methotrexate