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In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a district gene expression profile

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dc.contributor.authorSorich, M.J.
dc.contributor.authorPottier, N.
dc.contributor.authorPei, D.
dc.contributor.authorYang, W.
dc.contributor.authorKager, L.
dc.contributor.authorStocco, G.
dc.contributor.authorCheng, C.
dc.contributor.authorPanetta, J.
dc.contributor.authorPui, C.H.
dc.contributor.authorRelling, M.
dc.contributor.authorCheok, M.
dc.contributor.authorEvans, W.
dc.contributor.editorFischer, A.
dc.date.issued2008
dc.description.abstractBackground: Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This lack of knowledge is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX. Methods and findings: We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial “up-front” in vivo MTX treatment (1 g/m2) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1–18 y). We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of children with ALL. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p < 0.001, p = 0.02). Conclusions: Together, these data provide new insights into the genomic basis of MTX resistance and interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL.
dc.identifier.citationPLoS Medicine, 2008; 5(4):article no. e83-
dc.identifier.doi10.1371/journal.pmed.0050083
dc.identifier.issn1549-1676
dc.identifier.issn1549-1676
dc.identifier.urihttps://hdl.handle.net/1959.8/70394
dc.language.isoen
dc.publisherPublic Library of Science
dc.rightsCopyright 2008 Sorich et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. (http://creativecommons.org/licenses/by/2.5/)
dc.source.urihttps://doi.org/10.1371/journal.pmed.0050083
dc.subjectHumans
dc.subjectMethotrexate
dc.subjectAntimetabolites, Antineoplastic
dc.subjectDisease-Free Survival
dc.subjectTreatment Outcome
dc.subjectCohort Studies
dc.subjectGene Expression Profiling
dc.subjectDrug Resistance, Neoplasm
dc.subjectAdolescent
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectInfant
dc.subjectFemale
dc.subjectMale
dc.subjectPrecursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subjectNeoplastic Cells, Circulating
dc.subjectKaplan-Meier Estimate
dc.titleIn vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a district gene expression profile
dc.typeJournal article
pubs.publication-statusPublished
ror.fileinfo12143322690001831 13143320440001831 9915911062001831_53109067910001831.pdf
ror.mmsid9915911062001831

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