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Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy

A Corrigendum to this article was published on 01 March 2006

Key Points

  • Germline polymorphisms are known to influence the pharmacokinetics and pharmacological effects of a growing number of anticancer agents.

  • Polymorphisms in the human thiopurine methyltransferase (TPMT) gene lead to loss of the functional protein and predispose with high penetrance to severe haematopoietic toxicity in TPMT-deficient patients, unless their dose of mercaptopurine is reduced by 90–95%.

  • Candidate-gene strategies have shown that germline polymorphisms in additional genes — such as the glutathione S-transferase genes, the uridine-5′-diphosphate-glucuronosyl-transferase genes and the thymidylate synthetase gene — are associated with the efficacy or toxicity of chemotherapy for acute lymphoblastic leukaemia (ALL).

  • Recently, distinct gene-expression profiles of primary ALL cells have been linked to the sensitivity of leukaemia cells to several antileukaemic agents in vitro, and these expression signatures also predicted treatment outcome.

  • These findings provide momentum for future genome-wide studies to identify additional genomic determinants of ALL- treatment responses. These will allow the development of polygenic models that can be used to optimize the treatment of ALL and other human cancers.

Abstract

The use of combination chemotherapy to cure acute lymphoblastic leukaemia (ALL) in children emerged in the 1980s as a paradigm for curing any disseminated cancer, and many of the therapeutic principles were subsequently applied to the treatment of other disseminated human cancers. Similarly, elucidation of the pharmacogenomics of ALL and its translation into new chemotherapeutic approaches might serve as a model for optimizing the treatment of other human cancers. Germline polymorphisms and gene-expression patterns in ALL cells have been linked to the toxicity and efficacy of chemotherapy for ALL and are beginning to emerge as useful clinical diagnostics.

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Figure 1: The thiopurine pathway.
Figure 2: Polymorphisms in thiopurine methyltransferase.
Figure 3: Effects of thiopurine methyltransferase polymorphisms on the pharmacogenetics of mercaptopurine toxicity.
Figure 4: The folate pathway.
Figure 5: A gene-expression profile that is associated with drug sensitivity.
Figure 6: Comparison of single-gene, candidate-pathway-gene and genome-wide pharmacogenomic approaches to the analysis of drug-related phenotypes.

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References

  1. Simone, J. V. Childhood leukemia as a model for cancer research: the Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res. 39, 4301–4307 (1979).

    CAS  PubMed  Google Scholar 

  2. Simone, J. V. Childhood leukemia — successes and challenges for survivors. N. Engl. J. Med. 349, 627–628 (2003).

    Article  PubMed  Google Scholar 

  3. Pui, C. H. & Evans, W. E. Treatment of acute lymphoblastic leukemia. N. Engl. J. Med. 354, 166–178 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Pui, C. H., Relling, M. V. & Downing, J. R. Acute lymphoblastic leukemia. N. Engl. J. Med. 350, 1535–1548 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Pui, C. H. & Evans, W. E. Acute lymphoblastic leukemia. N. Engl. J. Med. 339, 605–615 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Pui, C. H., Campana, D. & Evans, W. E. Childhood acute lymphoblastic leukaemia — current status and future perspectives. Lancet Oncol. 2, 597–607 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Evans, W. E. & Relling, M. V. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487–491 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Relling, M. V. & Dervieux, T. Pharmacogenetics and cancer therapy. Nature Rev. Cancer 1, 99–108 (2001).

    Article  CAS  Google Scholar 

  9. Evans, W. E. & Relling, M. V. Moving towards individualized medicine with pharmacogenomics. Nature 429, 464–468 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Weinshilboum, R. Inheritance and drug response. N. Engl. J. Med. 348, 529–537 (2003).

    Article  PubMed  Google Scholar 

  11. Ulrich, C. M., Robien, K. & McLeod, H. L. Cancer pharmacogenetics: polymorphisms, pathways and beyond. Nature Rev. Cancer 3, 912–920 (2003).

    Article  CAS  Google Scholar 

  12. Undevia, S. D., Gomez-Abuin, G. & Ratain, M. J. Pharmacokinetic variability of anticancer agents. Nature Rev. Cancer 5, 447–458 (2005).

    Article  CAS  Google Scholar 

  13. Krynetski, E. Y. & Evans, W. E. Pharmacogenetics of cancer therapy: getting personal. Am. J. Hum. Genet. 63, 11–16 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McLeod, H. L., Krynetski, E. Y., Relling, M. V. & Evans, W. E. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14, 567–572 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Pazmino, P. A., Sladek, S. L. & Weinshilboum, R. M. Thiol S-methylation in uremia: erythrocyte enzyme activities and plasma inhibitors. Clin. Pharmacol. Ther. 28, 356–367 (1980).

    Article  CAS  PubMed  Google Scholar 

  16. Weinshilboum, R. M. & Sladek, S. L. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 32, 651–662 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lennard, L., Lilleyman, J. S., Van, L. J. & Weinshilboum, R. M. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336, 225–229 (1990). The first study to show a relation between a patient's TPMT activity and the active metabolite of mercaptopurine (thioguanine nucleotides) in erythrocytes.

    Article  CAS  PubMed  Google Scholar 

  18. Krynetski, E. Y., Krynetskaia, N. F., Yanishevski, Y. & Evans, W. E. Methylation of mercaptopurine, thioguanine, and their nucleotide metabolites by heterologously expressed human thiopurine S-methyltransferase. Mol. Pharmacol. 47, 1141–1147 (1995).

    CAS  PubMed  Google Scholar 

  19. Loennechen, T. et al. Isolation of a human thiopurine S-methyltransferase (TPMT) complementary DNA with a single nucleotide transition A719G (TPMT*3C) and its association with loss of TPMT protein and catalytic activity in humans. Clin. Pharmacol. Ther. 64, 46–51 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Tai, H. L. et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am. J. Hum. Genet. 58, 694–702 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Otterness, D. et al. Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin. Pharmacol. Ther. 62, 60–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Yates, C. R. et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 126, 608–614 (1997). The first study to show high concordance between TPMT genotype and TPMT catalytic activity in patients.

    Article  CAS  PubMed  Google Scholar 

  23. Krynetski, E. Y. et al. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc. Natl Acad. Sci. USA 92, 949–953 (1995). The first human TPMT variant allele to be cloned and characterized, followed by the identification of other variant alleles and the development of genotyping methods to diagnose TPMT deficiency.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schaeffeler, E. et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14, 407–417 (2004). A study in a large cohort of patients that establishes the sensitivity and specificity of diagnosing TPMT deficiency on the basis of TPMT genotype.

    Article  CAS  PubMed  Google Scholar 

  25. Hon, Y. Y. et al. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum. Mol. Genet. 8, 371–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Cheng, Q. et al. Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes. Nature Genet. 37, 878–882 (2005). Initial study to show that acquisition of an additional chromosome in leukaemia cells alters the concordance of genotype and phenotype depending on whether the acquired chromosome contains a wild-type or variant allele for the gene of interest.

    Article  CAS  PubMed  Google Scholar 

  27. McLeod, H. L., Relling, M. V., Liu, Q., Pui, C. H. & Evans, W. E. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood 85, 1897–1902 (1995).

    CAS  PubMed  Google Scholar 

  28. Stanulla, M. et al. Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA 293, 1485–1489 (2005). This report demonstrated that TPMT genotypes were associated with the early response to treatment of acute lymphoblastic leukaemia.

    Article  CAS  PubMed  Google Scholar 

  29. Evans, W. E., Horner, M., Chu, Y. Q., Kalwinsky, D. & Roberts, W. M. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J. Pediatr. 119, 985–989 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Evans, W. E. et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J. Clin. Oncol. 19, 2293–2301 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Relling, M. V. et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J. Natl Cancer Inst. 91, 2001–2008 (1999). First study to show that TPMT heterozygotes are at higher risk of mercaptopurine dose-limiting haematopoietic toxicity.

    Article  CAS  PubMed  Google Scholar 

  32. Schutz, E., Gummert, J., Armstrong, V. W., Mohr, F. W. & Oellerich, M. Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation. Eur. J. Clin. Chem. Clin. Biochem. 34, 199–205 (1996).

    CAS  PubMed  Google Scholar 

  33. Lennard, L., Gibson, B. E., Nicole, T. & Lilleyman, J. S. Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch. Dis. Child 69, 577–579 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bo, J. et al. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer 86, 1080–1086 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Relling, M. V. et al. Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia. Leukemia 12, 346–352 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Evans, W. E. Thiopurine S-methyltransferase: a genetic polymorphism that affects a small number of drugs in a big way. Pharmacogenetics 12, 421–423 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Relling, M. V. et al. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 354, 34–39 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. Marshall, E. Preventing toxicity with a gene test. Science 302, 588–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Abbott, A. With your genes? Take one of these, three times a day. Nature 425, 760–762 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Chen, C. L. et al. Higher frequency of glutathione S-transferase deletions in black children with acute lymphoblastic leukemia. Blood 89, 1701–1707 (1997).

    CAS  PubMed  Google Scholar 

  41. Hayes, J. D., Flanagan, J. U. & Jowsey, I. R. Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 45, 51–88 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Woo, M. H. et al. Glutathione S-transferase genotypes in children who develop treatment-related acute myeloid malignancies. Leukemia 14, 232–237 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Allan, J. M. et al. Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc. Natl Acad. Sci. USA 98, 11592–11597 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Anderer, G. et al. Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia. Pharmacogenetics 10, 715–726 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Davies, S. M. et al. Glutathione S-transferase polymorphisms and outcome of chemotherapy in childhood acute myeloid leukemia. J. Clin. Oncol. 19, 1279–1287 (2001).

    Article  PubMed  Google Scholar 

  46. Haase, D. et al. Increased risk for therapy-associated hematologic malignancies in patients with carcinoma of the breast and combined homozygous gene deletions of glutathione transferases M1 and T1. Leuk. Res. 26, 249–254 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Kishi, S. et al. Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia. Blood 103, 67–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Stanulla, M., Schrappe, M., Brechlin, A. M., Zimmermann, M. & Welte, K. Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study. Blood 95, 1222–1228 (2000).

    CAS  PubMed  Google Scholar 

  49. Takanashi, M. et al. Impact of glutathione S-transferase gene deletion on early relapse in childhood B-precursor acute lymphoblastic leukemia. Haematologica 88, 1238–1244 (2003).

    CAS  PubMed  Google Scholar 

  50. Naoe, T. et al. Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/myelodysplastic syndrome and de novo acute myeloid leukemia. Clin. Cancer Res. 6, 4091–4095 (2000).

    CAS  PubMed  Google Scholar 

  51. Stanulla, M. et al. GSTP1 and MDR1 genotypes and central nervous system relapse in childhood acute lymphoblastic leukemia. Int. J. Hematol. 81, 39–44 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Meissner, B. et al. The GSTT1 deletion polymorphism is associated with initial response to glucocorticoids in childhood acute lymphoblastic leukemia. Leukemia 18, 1920–1923 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Davies, S. M. et al. Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia. Blood 100, 67–71 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Rocha, J. C. et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 105, 4752–4758 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Relling, M. V., Hancock, M. L., Boyett, J. M., Pui, C. H. & Evans, W. E. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 93, 2817–2823 (1999).

    CAS  PubMed  Google Scholar 

  56. Pieters, R. et al. Hypoxanthine-guanine phosphoribosyl-transferase in childhood leukemia: relation with immunophenotype, in vitro drug resistance and clinical prognosis. Int. J. Cancer 51, 213–217 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Zaza, G. et al. Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment. Blood 106, 1778–1785 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Scherf, U. et al. A gene expression database for the molecular pharmacology of cancer. Nature Genet. 24, 236–244 (2000). Description of a cancer-drug discovery resource that integrates large-scale drug sensitivities with baseline gene-expression profiles in 60 cancer cell lines.

    Article  CAS  PubMed  Google Scholar 

  59. Zaza, G. et al. Acute lymphoblastic leukemia with TEL–AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis. Blood 104, 1435–1441 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. Ross, M. E. et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 102, 2951–2959 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Coulthard, S. A. et al. The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs. Mol. Pharmacol. 62, 102–109 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Dervieux, T. et al. Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res. 61, 5810–5816 (2001).

    CAS  PubMed  Google Scholar 

  63. Estlin, E. J., Lowis, S. P. & Hall, A. G. Optimizing antimetabolite-based chemotherapy for the treatment of childhood acute lymphoblastic leukaemia. Br. J. Haematol. 110, 29–40 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Jansen, G. et al. A structurally altered human reduced folate carrier with increased folic acid transport mediates a novel mechanism of antifolate resistance. J. Biol. Chem. 273, 30189–30198 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Wong, S. C. et al. Impaired membrane transport in methotrexate-resistant CCRF–CEM cells involves early translation termination and increased turnover of a mutant reduced folate carrier. J. Biol. Chem. 274, 10388–10394 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Chango, A. et al. A polymorphism (80G->A) in the reduced folate carrier gene and its associations with folate status and homocysteinemia. Mol. Genet. Metab. 70, 310–315 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Laverdiere, C., Chiasson, S., Costea, I., Moghrabi, A. & Krajinovic, M. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 100, 3832–3834 (2002).

    Article  PubMed  Google Scholar 

  68. Whetstine, J. R. et al. Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers. Clin. Cancer Res. 7, 3416–3422 (2001).

    CAS  PubMed  Google Scholar 

  69. Levy, A. S. et al. Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: a Children's Cancer Group Study. J. Pediatr. Hematol. Oncol. 25, 688–695 (2003).

    Article  PubMed  Google Scholar 

  70. Belkov, V. M. et al. Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood 93, 1643–1650 (1999).

    CAS  PubMed  Google Scholar 

  71. Kager, L. et al. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J. Clin. Invest. 115, 110–117 (2005). A candidate-gene approach that linked levels of active metabolites of methotrexate in leukaemic cells to the expression of folate-pathway genes in leukaemia cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cheng, Q. et al. A substrate specific functional polymorphism of human γ-glutamyl hydrolase alters catalytic activity and methotrexate polyglutamate accumulation in acute lymphoblastic leukaemia cells. Pharmacogenetics 14, 557–567 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Krajinovic, M., Costea, I. & Chiasson, S. Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 359, 1033–1034 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Lauten, M., Asgedom, G., Welte, K., Schrappe, M. & Stanulla, M. Thymidylate synthase gene polymorphism and its association with relapse in childhood B-cell precursor acute lymphoblastic leukemia. Haematologica 88, 353–354 (2003).

    CAS  PubMed  Google Scholar 

  75. Frosst, P. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet. 10, 111–113 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Molloy, A. M. et al. Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349, 1591–1593 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Ulrich, C. M. et al. Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 98, 231–234 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Skibola, C. F. et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc. Natl Acad. Sci. USA 96, 12810–12815 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wiemels, J. L. et al. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc. Natl Acad. Sci. USA 98, 4004–4009 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Krajinovic, M. et al. Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J. 4, 66–72 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Synold, T. W. et al. Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia. J. Clin. Invest. 94, 1996–2001 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Galpin, A. J. et al. Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity. Mol. Pharmacol. 52, 155–163 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Barredo, J. C. et al. Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood 84, 564–569 (1994).

    CAS  PubMed  Google Scholar 

  84. Armstrong, S. A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genet. 30, 41–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999). First study to show that gene-expression profiling can accurately discriminate ALL from AML.

    Article  CAS  PubMed  Google Scholar 

  86. Ramaswamy, S. & Golub, T. R. DNA microarrays in clinical oncology. J. Clin. Oncol. 20, 1932–1941 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Moos, P. J. et al. Identification of gene expression profiles that segregate patients with childhood leukemia. Clin. Cancer Res. 8, 3118–3130 (2002).

    CAS  PubMed  Google Scholar 

  88. Ross, M. E. et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood 104, 3679–3687 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Yeoh, E.-J. et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1, 133–143 (2002). First study to show distinct gene-expression patterns in ALL of different lineage and molecular subgroups.

    Article  CAS  PubMed  Google Scholar 

  90. Teuffel, O. et al. Gene expression profiles and risk stratification in childhood acute lymphoblastic leukemia. Haematologica 89, 801–808 (2004).

    CAS  PubMed  Google Scholar 

  91. Willenbrock, H., Juncker, A. S., Schmiegelow, K., Knudsen, S. & Ryder, L. P. Prediction of immunophenotype, treatment response, and relapse in childhood acute lymphoblastic leukemia using DNA microarrays. Leukemia 18, 1270–1277 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Qian, Z., Fernald, A. A., Godley, L. A., Larson, R. A. & Le Beau, M. M. Expression profiling of CD34+ hematopoietic stem/progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Proc. Natl Acad. Sci. USA 99, 14925–14930 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Brown, P. et al. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood 105, 812–820 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Edick, M. J. et al. Lymphoid gene expression as a predictor of risk of secondary brain tumors. Genes Chromosomes Cancer 42, 107–116 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Staunton, J. E. et al. Chemosensitivity prediction by transcriptional profiling. Proc. Natl Acad. Sci. USA 98, 10787–10792 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Holleman, A. et al. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N. Engl. J. Med. 351, 533–542 (2004). First study to show that gene-expression patterns in drug-sensitive and drug-resistant ALL cells differ significantly and predict treatment outcome.

    Article  CAS  PubMed  Google Scholar 

  97. Lugthart, S. et al. Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemia. Cancer Cell 7, 375–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. French, D. et al. Global gene expression as a function of germline genetic variation. Hum. Mol. Genet. 14, 1621–1629 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Cheok, M. H. et al. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nature Genet. 34, 85–90 (2003). First study to show that antileukaemic agents evoke treatment-specific changes in gene expression in ALL cells in vivo.

    Article  CAS  PubMed  Google Scholar 

  100. Evans, W. E. & Guy, R. K. Gene expression as a drug discovery tool. Nature Genet. 36, 214–215 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Stegmaier, K. et al. Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation. Nature Genet. 36, 257–263 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Hofmann, W. K. et al. Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study. Lancet 359, 481–486 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Golub, T. R. Mining the genome for combination therapies. Nature Med. 9, 510–511 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Kennedy, G. C. et al. Large-scale genotyping of complex DNA. Nature Biotechnol. 21, 1233–1237 (2003).

    Article  CAS  Google Scholar 

  105. Irving, J. A. et al. Loss of heterozygosity in childhood acute lymphoblastic leukemia detected by genome-wide microarray single nucleotide polymorphism analysis. Cancer Res. 65, 3053–3058 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Takeuchi, S. et al. Long-term study of the clinical significance of loss of heterozygosity in childhood acute lymphoblastic leukemia. Leukemia 17, 149–154 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Sherr, C. J. The INK4a–ARF network in tumour suppression. Nature Rev. Mol. Cell Biol. 2, 731–737 (2001).

    Article  CAS  Google Scholar 

  108. Innocenti, F. et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J. Clin. Oncol. 22, 1382–1388 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  Google Scholar 

  110. Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nature Med. 10, 33–39 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Pomeroy, S. L. et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415, 436–442 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Roepman, P. et al. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nature Genet. 37, 182–186 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Evans, W. E. & McLeod, H. L. Pharmacogenomics — drug disposition, drug targets, and side effects. N. Engl. J. Med. 348, 538–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Matherly, L. H. et al. Increased frequency of expression of elevated dihydrofolate reductase in T-cell versus B-precursor acute lymphoblastic leukemia in children. Blood 90, 578–589 (1997).

    CAS  PubMed  Google Scholar 

  115. Zaza, G. et al. Thiopurine Pathway [online], <http://www.pharmgkb.org/search/pathway/thiopurine/thiopurine.jsp> (2004).

  116. Krynetski, E. Y. et al. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6, 279–290 (1996).

    Article  CAS  PubMed  Google Scholar 

  117. French, D. et al. Methotrexate Pathway [online], <http://www.pharmgkb.org/search/pathway/mtx/methotrexate.jsp> (2004).

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Acknowledgements

This work was supported in part by National Institutes of Health grants and by the American Lebanese Syrian Associated Charities. We would also like to thank C.-H. Pui, M.V. Relling and M. Schwab for helpful discussions; and J.R. Davies for editorial support.

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Correspondence to William E. Evans.

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DATABASES

National Cancer Institute

acute lymphoblastic leukaemia

acute myeloid leukaemia

FURTHER INFORMATION

HapMap Project

Japanese Single Nucleotide Polymorphisms database

NCBIs Single Nucleotide Polymorphism Database

Pharmacogenetics and Pharmacogenomics Knowledge Base

Pharmacogenetics of Anticancer Agents Research Group

Glossary

Pharmacogenomics

Often used synonymously with pharmacogenetics, but also used to refer to polygenic strategies within pharmacogenetics.

Germline polymorphism

The existence of two or more variants of a gene locus (alleles, sequence variants or chromosomal structural variants) at significant frequencies (usually >1%) in the population.

Pharmacogenetics

Focuses on the inherited variability in drug targets, target pathways, drug absorption, distribution, metabolism, transport and elimination, or in genes that indirectly influence drug response, and how these genetic variations influence drug-response phenotypes.

Minimal residual disease

Tumour cells remaining in patients after treatment (for example, surgical debulking, chemotherapy or radiotherapy), often at sub-microscopic levels.

Dose escalation

The administration of successively higher doses of drug to a cohort of patients until a subset of these patients experience unacceptable side effects. The highest dose at which patients do not experience serious side effects is the maximum tolerated dose.

Purine-salvage pathway

The synthesis of nucleotides from purine bases, which are recycled to produce the corresponding nucleotides after phosphoribosylation. A key enzyme in this pathway is hypoxanthine-guanine phosphoribosyltransferase.

ABC transporters

Transmembrane proteins that transport a wide variety of substrates (for example, metabolites, lipids, sterols and drugs). Overexpression can lead to drug-resistant cancer. There are 48 known human ABC transporters in 7 distinct subfamilies.

Penetrance

The proportion of individuals who develop a phenotype when they inherit a polymorphism that is associated with this phenotype. If a polymorphism has complete penetrance, the phenotype is present in all carriers, whereas reduced or incomplete penetrance exists if the phenotype is not always present.

Loss of heterozygosity

Loss of one allele in a cell (for example, a tumour cell) of a gene (or chromosomal region) that is heterozygous in normal cells of the same individual.

Laser-capture microdissection

Laser-aided removal of cells from a tissue sample, especially when it consists of different cell types (for example, normal and cancer cells). Individual cells are attached to a transfer film for further analysis.

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Cheok, M., Evans, W. Acute lymphoblastic leukaemia: a model for the pharmacogenomics of cancer therapy. Nat Rev Cancer 6, 117–129 (2006). https://doi.org/10.1038/nrc1800

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