the Oregon Clinical and Translational Research Institute. BJD is an investigator of the Howard Hughes Medical Institute. Conflict of interest The authors declare no conflict of interest. JW Tyner 1 , ML Rutenberg-Schoenberg 1 , H Erickson 1 , SG Willis 1 , T O’Hare 1,2 , MW Deininger 1 , BJ Druker 1,2 and MM Loriaux 1,3 1 Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA; 2 Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR, USA and 3 Department of Pathology, Oregon Health & Science University, Portland, OR, USA E-mail: loriauxm@ohsu.edu References 1 Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417. 2 Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non- small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129–2139. 3 Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–1500. 4 Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369: 29–36. 5 Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005; 353: 172–187. 6 Birkenkamp KU, Geugien M, Lemmink HH, Kruijer W, Vellenga E. Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts. Leukemia 2001; 15: 1923–1931. 7 Hayakawa F, Towatari M, Iida H, Wakao H, Kiyoi H, Naoe T et al. Differential constitutive activation between STAT-related proteins and MAP kinase in primary acute myelogenous leukaemia. Br J Haematol 1998; 101: 521–528. 8 Spiekermann K, Pau M, Schwab R, Schmieja K, Franzrahe S, Hiddemann W. Constitutive activation of STAT3 and STAT5 is induced by leukemic fusion proteins with protein tyrosine kinase activity and is sufficient for transformation of hematopoietic precursor cells. Exp Hematol 2002; 30: 262–271. 9 Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G et al. Patterns of somatic mutation in human cancer genomes. Nature 2007; 446: 153–158. 10 Loriaux MM, Levine RL, Tyner JW, Frohling S, Scholl C, Stoffregen EP et al. High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood 2008; 111: 4788–4796. 11 Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006; 314: 268–274. 12 Tomasson MH, Xiang Z, Walgren R, Zhao Y, Kasai Y, Miner T et al. Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia. Blood 2008; 111: 4797–4808. 13 Morris PN, Dunmore BJ, Tadros A, Marchuk DA, Darland DC, D’Amore PA et al. Functional analysis of a mutant form of the receptor tyrosine kinase Tie2 causing venous malformations. J Mol Med 2005; 83: 58–63. 14 Wang H, Zhang Y, Toratani S, Okamoto T. Transformation of vascular endothelial cells by a point mutation in the Tie2 gene from human intramuscular haemangioma. Oncogene 2004; 23: 8700–8704. 15 Campbell PJ, Stephens PJ, Pleasance ED, O’Meara S, Li H, Santarius T et al. Identification of somatically acquired rearrange- ments in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 2008; 40: 722–729. 16 Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 2008; 452: 872–876. Reduced folate carrier and methylenetetrahydrofolate reductase gene polymorphisms: associations with clinical outcome in childhood acute lymphoblastic leukemia Leukemia (2009) 23, 1348–1351; doi:10.1038/leu.2009.67; published online 2 April 2009 Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed during childhood. Although the 5-year survival rate of children treated for ALL is now above 80%, a considerable proportion of these children continue to relapse or die during or after completing therapy. The anti-folate cancer drug, methotrexate (MTX), is a critical component of ALL chemotherapy protocols and poor cellular response to MTX can substantially contribute to treatment failure in children treated for ALL. 1 Moreover, recent studies have also provided evidence suggesting that common polymorphisms in genes of the folate pathway may play an important role in determining treatment efficacy and toxicity in patients treated for ALL. 2–4 Two common polymorphisms have been extensively des- cribed in the MTHFR gene. The first polymorphism, MTHFR C677T, involves a C to T transition causing an alanine to valine substitution at amino acid position 222, whereas the second, MTHFR A1298C, involves an A to C transversion causing a glutamic acid to alanine replacement at amino acid position 429. Both of these variants have been shown to have an impact on enzyme activity. Earlier studies have shown enzymatic activity to be reduced by up to 60% in individuals homozygous for MTHFR 677TT and to a lesser extent in those heterozygous for MTHFR 677TC, whereas other studies have shown that the MTHFR 1298C polymorphism results in decreased enzyme activity in vitro, although not to the levels observed in carriers of the MTHFR 677T polymorphism (reviewed by Schwahn and Rozen 5 ). Investigators have also reported an increased frequency of MTHFR 677TT homozygosity in leukaemia patients intolerant to MTX, suggesting that the MTHFR 677TT polymorphism is associated with increased MTX toxicity or reduced survival, owing to interference with MTX activity. 3,5 Investigators have also reported a functional polymorphism in the reduced folate carrier gene (RFC G80A) that causes an arginine to histidine substitution at amino acid position 27 and affects folate and homocysteine levels in healthy individuals. 6,7 Although the RFC 80A allele variant has been shown to improve Letters to the Editor 1348 Leukemia