Seminars in Hematology
Volume 46, Issue 1 , Pages 3-15 , January 2009

Global Genomic Characterization of Acute Lymphoblastic Leukemia

  • Charles G. Mullighan
    • ,
  • James R. Downing

      Affiliations

    • Corresponding Author InformationAddress correspondence to James R. Downing, MD, Scientific Director, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 271, Memphis, TN, 38105

References 

  1. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. 2008;371:1030–1043
  2. Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood. 2004;104:2690–2696
  3. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–950
  4. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106:3760–3767
  5. Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Engl J Med. 2004;350:1535–1548
  6. Harrison CJ, Foroni L. Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Rev Clin Exp Hematol. 2002;6:91–113
  7. Raimondi SC. Cytogenetics of acute leukemias. In:  Pui CH editors. Childhood leukemias. 2nd ed.. Cambridge: Cambridge University Press; 2006;p. 235–271
  8. Graux C, Cools J, Michaux L, Vandenberghe P, Hagemeijer A. Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia. 2006;20:1496–1510
  9. Greaves MF, Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer. 2003;3:639–649
  10. Andreasson P, Schwaller J, Anastasiadou E, Aster J, Gilliland DG. The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo. Cancer Genet Cytogenet. 2001;130:93–104
  11. Williams RT, Roussel MF, Sherr CJ. Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2006;103:6688–6693
  12. Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109:3189–3197
  13. Hebert J, Cayuela JM, Berkeley J, Sigaux F. Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. Blood. 1994;84:4038–4044
  14. Ogawa S, Hangaishi A, Miyawaki S, Hirosawa S, Miura Y, Takeyama K, et al. Loss of the cyclin-dependent kinase 4-inhibitor (p16; MTS1) gene is frequent in and highly specific to lymphoid tumors in primary human hematopoietic malignancies. Blood. 1995;86:1548–1556
  15. Okuda T, Shurtleff SA, Valentine MB, Raimondi SC, Head DR, Behm F, et al. Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia. Blood. 1995;85:2321–2330
  16. Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269–271
  17. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531–537
  18. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002;1:133–143
  19. Huhta T, Vettenranta K, Heinonen K, Kanerva J, Larramendy ML, Mahlamaki E, et al. Comparative genomic hybridization and conventional cytogenetic analyses in childhood acute myeloid leukemia. Leuk Lymphoma. 1999;35:311–315
  20. Jalali GR, An Q, Konn ZJ, Worley H, Wright SL, Harrison CJ, et al. Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia. Leukemia. 2008;22:114–123
  21. Kuchinskaya E, Heyman M, Nordgren A, Schoumans J, Staaf J, Borg A, et al. Array-CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G-banding. Br J Haematol. 2008;140:572–577
  22. Kuchinskaya E, Nordgren A, Heyman M, Schoumans J, Corcoran M, Staaf J, et al. Tiling-resolution array-CGH reveals the pattern of DNA copy number alterations in acute lymphoblastic leukemia with 21q amplification: the result of telomere dysfunction and breakage/fusion/breakage cycles?. Leukemia. 2007;21:1327–1330
  23. Larramendy ML, Huhta T, Heinonen K, Vettenranta K, Mahlamaki E, Riikonen P, et al. DNA copy number changes in childhood acute lymphoblastic leukemia. Haematologica. 1998;83:890–895
  24. Larramendy ML, Huhta T, Vettenranta K, El-Rifai W, Lundin J, Pakkala S, et al. Comparative genomic hybridization in childhood acute lymphoblastic leukemia. Leukemia. 1998;12:1638–1644
  25. Lundin C, Heidenblad M, Strombeck B, Borg A, Hovland R, Heim S, et al. Tiling resolution array CGH of dic(7;9)(p11 approximately 13;p11 approximately 13) in B-cell precursor acute lymphoblastic leukemia reveals clustered breakpoints at 7p11.2 approximately 12.1 and 9p13.1. Cytogenet Genome Res. 2007;118:13–18
  26. Rabin KR, Man TK, Yu A, Folsom MR, Zhao YJ, Rao PH, et al. Clinical utility of array comparative genomic hybridization for detection of chromosomal abnormalities in pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer. 2008;51:171–177
  27. Schoumans J, Johansson B, Corcoran M, Kuchinskaya E, Golovleva I, Grander D, et al. Characterisation of dic(9;20)(p11-13;q11) in childhood B-cell precursor acute lymphoblastic leukaemia by tiling resolution array-based comparative genomic hybridisation reveals clustered breakpoints at 9p13.2 and 20q11.2. Br J Haematol. 2006;135:492–499
  28. Steinemann D, Cario G, Stanulla M, Karawajew L, Tauscher M, Weigmann A, et al. Copy number alterations in childhood acute lymphoblastic leukemia and their association with minimal residual disease. Genes Chromosomes Cancer. 2008;47:471–480
  29. Strefford JC, van Delft FW, Robinson HM, Worley H, Yiannikouris O, Selzer R, et al. Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Proc Natl Acad Sci U S A. 2006;103:8167–8172
  30. Strefford JC, Worley H, Barber K, Wright S, Stewart AR, Robinson HM, et al. Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization. Oncogene. 2007;26:4306–4318
  31. van Vlierberghe P, Meijerink JP, Lee C, Ferrando AA, Look AT, van Wering ER, et al. A new recurrent 9q34 duplication in pediatric T-cell acute lymphoblastic leukemia. Leukemia. 2006;20:1245–1253
  32. Pinkel D, Albertson DG. Comparative genomic hybridization. Annu Rev Genomics Hum Genet. 2005;6:331–354
  33. Davidsson J, Andersson A, Paulsson K, Heidenblad M, Isaksson M, Borg A, et al. Tiling resolution array comparative genomic hybridization, expression and methylation analyses of dup(1q) in Burkitt lymphomas and pediatric high hyperdiploid acute lymphoblastic leukemias reveal clustered near-centromeric breakpoints and overexpression of genes in 1q22-32.3. Hum Mol Genet. 2007;16:2215–2225
  34. Balgobind BV, Van Vlierberghe P, van den Ouweland AM, Beverloo HB, Terlouw-Kromosoeto JN, van Wering ER, et al. Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood. 2008;111:4322–4328
  35. Gandemer V, Rio AG, de Tayrac M, Sibut V, Mottier S, Ly Sunnaram B, et al. Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia. BMC Genomics. 2007;8:385
  36. Usvasalo A, Savola S, Raty R, Vettenranta K, Harila-Saari A, Koistinen P, et al. CDKN2A deletions in acute lymphoblastic leukemia of adolescents and young adults: an array CGH study. Leuk Res. 2008;32:1228–1235
  37. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449:851–861
  38. Irving JA, Bloodworth L, Bown NP, Case MC, Hogarth LA, Hall AG. Loss of heterozygosity in childhood acute lymphoblastic leukemia detected by genome-wide microarray single nucleotide polymorphism analysis. Cancer Res. 2005;65:3053–3058
  39. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007;446:758–764
  40. Olshen AB, Venkatraman ES, Lucito R, Wigler M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics. 2004;5:557–572
  41. Kwon K, Hutter C, Sun Q, Bilic I, Cobaleda C, Malin S, et al. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity. 2008;28:751–762
  42. Nutt SL, Kee BL. The transcriptional regulation of B cell lineage commitment. Immunity. 2007;26:715–725
  43. Cazzaniga G, Daniotti M, Tosi S, Giudici G, Aloisi A, Pogliani E, et al. The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case. Cancer Res. 2001;61:4666–4670
  44. Mullighan CG, Su X, Ma J, Yang W, Relling MV, Carroll WL, et al. Genome-wide profiling of high-risk pediatric acute lymphoblastic leukemia (ALL): The ALL Pilot Project for the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) initiative [abstract]. Blood (ASH Annual Meeting Abstracts). 2007;110:229
  45. Mullighan CG, Miller CB, Phillips LA, Dalton JD, Ma J, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–114
  46. Reynaud D, Demarco IA, Reddy KL, Schjerven H, Bertolino E, Chen Z, et al. Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Nat Immunol. 2008;
  47. Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994;79:143–156
  48. Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995;83:289–299
  49. Sun L, Crotty ML, Sensel M, Sather H, Navara C, Nachman J, et al. Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia. Clin Cancer Res. 1999;5:2112–2120
  50. Sun L, Goodman PA, Wood CM, Crotty ML, Sensel M, Sather H, et al. Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia. J Clin Oncol. 1999;17:3753–3766
  51. Sun L, Heerema N, Crotty L, Wu X, Navara C, Vassilev A, et al. Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1999;96:680–685
  52. Nakase K, Ishimaru F, Avitahl N, Dansako H, Matsuo K, Fujii K, et al. Dominant negative isoform of the Ikaros gene in patients with adult B-cell acute lymphoblastic leukemia. Cancer Res. 2000;60:4062–4065
  53. Nishii K, Kita K, Miwa H, Shikami M, Taniguchi M, Usui E, et al. Expression of B cell-associated transcription factors in B-cell precursor acute lymphoblastic leukemia cells: association with PU.1 expression, phenotype, and immunogenotype. Int J Hematol. 2000;71:372–378
  54. Olivero S, Maroc C, Beillard E, Gabert J, Nietfeld W, Chabannon C, et al. Detection of different Ikaros isoforms in human leukaemias using real-time quantitative polymerase chain reaction. Br J Haematol. 2000;110:826–830
  55. Takanashi M, Yagi T, Imamura T, Tabata Y, Morimoto A, Hibi S, et al. Expression of the Ikaros gene family in childhood acute lymphoblastic leukaemia. Br J Haematol. 2002;117:525–530
  56. Mullighan CG, Williams RT, Downing JR, Sherr CJ. Failure of CDKN2A/B (INK4A/B-ARF)-mediated tumor suppression and resistance to targeted therapy in acute lymphoblastic leukemia induced by BCR-ABL. Genes Dev. 2008;22:1411–1415
  57. Kolbus A, Blazquez-Domingo M, Carotta S, Bakker W, Luedemann S, von Lindern M, et al. Cooperative signaling between cytokine receptors and the glucocorticoid receptor in the expansion of erythroid progenitors: molecular analysis by expression profiling. Blood. 2003;102:3136–3146
  58. Lee H, Cha S, Lee MS, Cho GJ, Choi WS, Suk K. Role of antiproliferative B cell translocation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia. J Immunol. 2003;171:5802–5811
  59. Rouault JP, Rimokh R, Tessa C, Paranhos G, Ffrench M, Duret L, et al. BTG1, a member of a new family of antiproliferative genes. EMBO J. 1992;11:1663–1670
  60. Bray PJ, Cotton RG. Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms. Hum Mutat. 2003;21:557–568
  61. Kino T, Chrousos GP. Glucocorticoid and mineralocorticoid receptors and associated diseases. Essays Biochem. 2004;40:137–155
  62. Kawamata N, Ogawa S, Zimmermann M, Kato M, Sanada M, Hemminki K, et al. Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood. 2008;111:776–784
  63. Paulsson K, Cazier JB, Macdougall F, Stevens J, Stasevich I, Vrcelj N, et al. Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease. Proc Natl Acad Sci U S A. 2008;105:6708–6713
  64. Kaye J. CD160 and BTLA: LIGHTs out for CD4+ T cells. Nat Immunol. 2008;9:122–124
  65. Moreaux J, Veyrune JL, Reme T, De Vos J, Klein B. CD200: a putative therapeutic target in cancer. Biochem Biophys Res Commun. 2008;366:117–122
  66. Aliahmad P, Kaye J. Development of all CD4 T lineages requires nuclear factor TOX. J Exp Med. 2008;205:245–256
  67. Li J, Wang CY. TBL1-TBLR1 and beta-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nat Cell Biol. 2008;10:160–169
  68. Mullighan CG, Miller CB, Su X, Radtke I, Dalton JD, Song G, et al. ERG deletions define a novel subtype of B-progenitor acute lymphoblastic leukemia. Blood (ASH Annual Meeting Abstracts). 2007;110:691
  69. Loughran SJ, Kruse EA, Hacking DF, de Graaf CA, Hyland CD, Willson TA, et al. The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol. 2008;9:810–819
  70. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644–648
  71. Kitagawa Y, Inoue K, Sasaki S, Hayashi Y, Matsuo Y, Lieber MR, et al. Prevalent involvement of illegitimate V(D)J recombination in chromosome 9p21 deletions in lymphoid leukemia. J Biol Chem. 2002;277:46289–46297
  72. Mullighan CG, Radtke I, Ma J, Shurtleff SA, Downing JR. High-resolution SNP array profiling of relapsed acute leukemia identifies genomic abnormalities distinct from those present at diagnosis. Blood (ASH Annual Meeting Abstracts). 2007;110:234
  73. Graux C, Cools J, Melotte C, Quentmeier H, Ferrando A, Levine R, et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet. 2004;36:1084–1089
  74. Van Vlierberghe P, van Grotel M, Beverloo HB, Lee C, Helgason T, Buijs-Gladdines J, et al. The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Blood. 2006;108:3520–3529
  75. Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A, et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature. 2007;447:966–971
  76. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13:1203–1210
  77. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007;204:1813–1824
  78. Clappier E, Cuccuini W, Kalota A, Crinquette A, Cayuela JM, Dik WA, et al. The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood. 2007;110:1251–1261
  79. Lahortiga I, De Keersmaecker K, Van Vlierberghe P, Graux C, Cauwelier B, Lambert F, et al. Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nat Genet. 2007;39:593–595
  80. Van Vlierberghe P, van Grotel M, Tchinda J, Lee C, Beverloo HB, van der Spek PJ, et al. The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood. 2008;111:4668–4680
  81. Raghavan M, Smith LL, Lillington DM, Chaplin T, Kakkas I, Molloy G, et al. Segmental uniparental disomy is a commonly acquired genetic event in relapsed acute myeloid leukemia. Blood. 2008;112:814–821
  82. Emerson JJ, Cardoso-Moreira M, Borevitz JO, Long M. Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster. Science. 2008;320:1629–1631
  83. Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, Santarius T, et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008;40:722–729
  84. Lin M, Wei LJ, Sellers WR, Lieberfarb M, Wong WH, Li C. dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics. 2004;20:1233–1240
  85. Nannya Y, Sanada M, Nakazaki K, Hosoya N, Wang L, Hangaishi A, et al. A robust algorithm for copy number detection using high-density oligonucleotide single nucleotide polymorphism genotyping arrays. Cancer Res. 2005;65:6071–6079
  86. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, et al. Detection of large-scale variation in the human genome. Nat Genet. 2004;36:949–951
  87. Beroukhim R, Lin M, Park Y, Hao K, Zhao X, Garraway LA, et al. Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays. PLoS Comput Biol. 2006;2:e41
  88. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8:286–298
  89. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5:621–628
  90. Shendure J. The beginning of the end for microarrays?. Nat Methods. 2008;5:585–587

 Supported in part by grants from the Haematology Society of Australasia, the Royal Australasian College of Physicians, the National Health and Medical Research Council (Australia), and the American Lebanese and Syrian Associated Charities of St Jude Children's Research Hospital.

PII: S0037-1963(08)00148-0

doi: 10.1053/j.seminhematol.2008.09.005

Seminars in Hematology
Volume 46, Issue 1 , Pages 3-15 , January 2009

Article Tools

* Image Usage & Resolution