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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.

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CLINICAL TRIALS AND OBSERVATIONS

Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia

Deborah French1, Wenjian Yang1, Cheng Cheng2,3, Susana C. Raimondi35, Charles G. Mullighan3,4, James R. Downing3,4, William E. Evans1,3,5, Ching-Hon Pui3,5,6, and Mary V. Relling1,3,5

Departments of 1 Pharmaceutical Sciences and 2 Biostatistics, 3 Hematological Malignancies Program, and 4 Department of Pathology, St Jude Children's Research Hospital, Memphis, TN; 5 University of Tennessee, Memphis; and 6 Department of Oncology, St Jude Children's Research Hospital, Memphis, TN

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. We analyzed 3 types of whole genome variation: leukemia cell gene expression and somatic copy number variation, and inherited single nucleotide polymorphism (SNP) genotypes and determined their association with MTXPGs in leukemia cells. Seven genes (FHOD3, IMPA2, ME2, RASSF4, SLC39A6, SMAD2, and SMAD4) displayed all 3 types of genomic variation associated with MTXPGs (P < .05 for gene expression, P < .01 for copy number variation and SNPs): 6 on chromosome 18 and 1 on chromosome 10. Increased chromosome 18 (P = .002) or 10 (P = .036) 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%). We conclude that acquired genetic variation in leukemia cells has a stronger influence on MTXPG accumulation than inherited genetic variation.


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