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Blood, 7 May 2009, Vol. 113, No. 19, pp. 4512-4520. Prepublished online as a Blood First Edition Paper on December 9, 2008; DOI 10.1182/blood-2008-07-172106. This Article Full Text (PDF) Supplemental Methods and Tables Additional Supplemental Tables Supplemental Figures All Versions of this Article: blood-2008-07-172106v1 113/19/4512    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by French, D. Articles by Relling, M. V. Search for Related Content PubMed PubMed Citation Articles by French, D. Articles by Relling, M. V. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 31, 2008 Accepted November 16, 2008 Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia Deborah French, Wenjian Yang, Cheng Cheng, Susana C. Raimondi, Charles G Mullighan, James R Downing, William E. Evans, Ching-Hon Pui, and Mary V. Relling* Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, United States Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, United States Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States Hematological Malignancies program, St. Jude Children's Research Hospital, Memphis, TN, United States Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States University of Tennessee, Memphis, TN, United States * Corresponding author; email: mary.relling{at}stjude.org. Rationale. Methotrexate polyglutamates (MTXPGs) determine in vivo efficacy in acute lymphoblastic leukemia (ALL). MTXPG accumulation differs by leukemic subtypes, but genomic determinants of MTXPG variation in ALL remain unclear. Objectives. We analyzed three types of whole-genome variation: leukemia cell gene expression and somatic copy number variation (CNV), and inherited SNP genotypes and determined their association with MTXPGs in leukemia cells. Findings. Seven genes (FHOD3, IMPA2, ME2, RASSF4, SLC39A6, SMAD2, SMAD4) displayed all three types of genomic variation associated with MTXPGs (p<0.05 for gene expression, p<0.01 for CNV and SNPs); 6 on chromosome 18 and one on chromosome 10. Increased chromosome 18 (p=0.0019) or 10 (p=0.0362) copy number was associated with MTXPGs even after adjusting for ALL subtype. The expression of the top 7 genes in leukemia cells accounted for more variation in MTXPGs (46%) than did the expression of the top 7 genes in normal HapMap cell lines (20%). The top 7 inherited SNPs in patients accounted for approximately the same degree of variation (17%) in MTXPGs as did the top 7 SNP genotypes in HapMap cell lines (20%). Conclusions. We conclude that acquired genetic variation in leukemia cells has a stronger influence on MTXPG accumulation than inherited genetic variation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Old drug, new lessons Gertjan J. L. Kaspers Blood 2009 113: 4480-4481. [Full Text] [PDF] This article has been cited by other articles: G. J. L. Kaspers Old drug, new lessons Blood, May 7, 2009; 113(19): 4480 - 4481. [Full Text] [PDF]

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