Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Genomic profiling of high-risk acute lymphoblastic leukemia

Leukemia volume 24, pages 1676–1685 (2010)Cite this article

Subjects

Abstract

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising multiple subtypes with different genetic alterations and responses to therapy. Recent genome-wide profiling studies of ALL have identified a number of novel genetic alterations that target key cellular pathways in lymphoid growth and differentiation and are associated with treatment outcome. Notably, genetic alteration of the lymphoid transcription factor gene IKZF1 is a hallmark of multiple subtypes of ALL with poor prognosis, including BCR-ABL1-positive lymphoid leukemia and a subset of ‘BCR-ABL1-like’ ALL cases that, in addition to IKZF1 alteration, harbor genetic mutations resulting in aberrant lymphoid cytokine receptor signaling, including activating mutations of Janus kinases and rearrangement of cytokine receptor-like factor 2 (CRLF2). Recent insights from genome-wide profiling studies of B-progenitor ALL and the potential for new therapeutic approaches in high-risk disease are discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Pui CH, Relling MV, Downing JR . Acute lymphoblastic leukemia. N Engl J Med 2004; 350: 1535–1548.

    CAS  PubMed  Google Scholar 

  2. Pui CH, Robison LL, Look AT . Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030–1043.

    CAS  PubMed  Google Scholar 

  3. Pui CH, Pei D, Sandlund JT, Ribeiro RC, Rubnitz JE, Raimondi SC et al. Long-term results of St Jude total therapy studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 2010; 24: 371–382.

    CAS  PubMed  Google Scholar 

  4. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–2741.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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.

    CAS  PubMed  Google Scholar 

  6. 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.

    CAS  PubMed  Google Scholar 

  7. Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 2008; 22: 2142–2150.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Nachman J . Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 2005; 130: 166–173.

    PubMed  Google Scholar 

  9. Stock W, La M, Sanford B, Bloomfield CD, Vardiman JW, Gaynon P et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and cancer and leukemia group B studies. Blood 2008; 112: 1646–1654.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Harrison CJ, Foroni L . Cytogenetics and molecular genetics of acute lymphoblastic leukemia. Rev Clin Exp Hematol 2002; 6: 91–113.

    CAS  PubMed  Google Scholar 

  11. Harrison CJ . Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol 2009; 144: 147–156.

    PubMed  Google Scholar 

  12. Gleissner B, Gokbuget N, Bartram CR, Janssen B, Rieder H, Janssen JW et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German multicenter trial group and confirmed polymerase chain reaction analysis. Blood 2002; 99: 1536–1543.

    CAS  PubMed  Google Scholar 

  13. Mullighan CG, Downing JR . Global genomic characterization of acute lymphoblastic leukemia. Semin Hematol 2009; 46: 3–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Mullighan CG, Downing JR . Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions. Leukemia 2009; 23: 1209–1218.

    CAS  PubMed  Google Scholar 

  15. 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.

    CAS  PubMed  Google Scholar 

  16. 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.

    CAS  PubMed  Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114: 647–650.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 2008; 453: 110–114.

    CAS  PubMed  Google Scholar 

  21. Kuiper RP, Schoenmakers EF, van Reijmersdal SV, Hehir-Kwa JY, van Kessel AG, van Leeuwen FN et al. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 2007; 21: 1258–1266.

    CAS  PubMed  Google Scholar 

  22. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Nebral K, Denk D, Attarbaschi A, Konig M, Mann G, Haas OA et al. Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. Leukemia 2009; 23: 134–143.

    CAS  PubMed  Google Scholar 

  24. Miller CB, Mullighan CG, Su X, Ma J, Wang M, Zhang J et al. Pax5 haploinsufficiency cooperates with BCR-ABL1 to induce acute lymphoblastic leukemia. Blood 2008; 112: 114 (abstract 293).

    Google Scholar 

  25. Dang J, Mullighan CG, Phillips LA, Mehta P, Downing JR . Retroviral and chemical mutagenesis identifies Pax5 as a tumor suppressor in B-progenitor acute lymphoblastic leukemia. Blood 2008; 112: 256 (abstract 1798).

    Google Scholar 

  26. Collins-Underwood JR, Miller CB, Downing JR, Mullighan CG . Ikzf1 haploinsufficiency contributes to the pathogenesis of BCR-ABL1 positive acute lymphoblastic leukemia. Blood 2009; 114: 283 (abstract 678).

    Google Scholar 

  27. Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360: 470–480.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Bardini M, Spinelli R, Bungaro S, Mangano E, Corral L, Cifola I et al. DNA copy-number abnormalities do not occur in infant ALL with t(4;11)/MLL-AF4. Leukemia 2010; 24: 169–176.

    CAS  PubMed  Google Scholar 

  29. Parker H, An Q, Barber K, Case M, Davies T, Konn Z et al. The complex genomic profile of ETV6-RUNX1 positive acute lymphoblastic leukemia highlights a recurrent deletion of TBL1XR1. Genes Chromosomes Cancer 2008; 47: 1118–1125.

    CAS  PubMed  Google Scholar 

  30. Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, Soverini S et al. Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell’Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood 2009; 114: 2159–2167.

    CAS  PubMed  Google Scholar 

  31. Martinelli G, Iacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J Clin Oncol 2009; 27: 5202–5207.

    CAS  PubMed  Google Scholar 

  32. Georgopoulos K, Moore DD, Derfler B . Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science 1992; 258: 808–812.

    CAS  PubMed  Google Scholar 

  33. 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.

    CAS  PubMed  Google Scholar 

  34. Molnar A, Georgopoulos K . The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol 1994; 14: 8292–8303.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Molnar A, Wu P, Largespada DA, Vortkamp A, Scherer S, Copeland NG et al. The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. J Immunol 1996; 156: 585–592.

    CAS  PubMed  Google Scholar 

  36. Klug CA, Morrison SJ, Masek M, Hahm K, Smale ST, Weissman IL . Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci USA 1998; 95: 657–662.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Georgopoulos K . Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nat Rev Immunol 2002; 2: 162–174.

    CAS  PubMed  Google Scholar 

  38. 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.

    CAS  PubMed  Google Scholar 

  39. 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 USA 1999; 96: 680–685.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Iacobucci I, Lonetti A, Messa F, Cilloni D, Arruga F, Ottaviani E et al. Expression of spliced oncogenic Ikaros isoforms in Philadelphia-positive acute lymphoblastic leukemia patients treated with tyrosine kinase inhibitors: implications for a new mechanism of resistance. Blood 2008; 112: 3847–3855.

    CAS  PubMed  Google Scholar 

  41. Klein F, Feldhahn N, Herzog S, Sprangers M, Mooster JL, Jumaa H et al. BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Oncogene 2006; 25: 1118–1124.

    CAS  PubMed  Google Scholar 

  42. 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.

    CAS  PubMed  Google Scholar 

  43. Tonnelle C, Bardin F, Maroc C, Imbert AM, Campa F, Dalloul A et al. Forced expression of the Ikaros 6 isoform in human placental blood CD34(+) cells impairs their ability to differentiate toward the B-lymphoid lineage. Blood 2001; 98: 2673–2680.

    CAS  PubMed  Google Scholar 

  44. Tonnelle C, Dijon M, Moreau T, Garulli C, Bardin F, Chabannon C . Stage specific over-expression of the dominant negative Ikaros 6 reveals distinct role of Ikaros throughout human B-cell differentiation. Mol Immunol 2009; 46: 1736–1743.

    CAS  PubMed  Google Scholar 

  45. Trageser D, Iacobucci I, Nahar R, Duy C, von Levetzow G, Klemm L et al. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. J Exp Med 2009; 206: 1739–1753.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 2009; 41: 1006–1010.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Trevino LR, Yang W, French D, Hunger SP, Carroll WL, Devidas M et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 2009; 41: 1001–1005.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Prasad RB, Hosking FJ, Vijayakrishnan J, Papaemmanuil E, Koehler R, Greaves M et al. Verification of the susceptibility loci on 7p12.2, 10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood 2010; 115: 1765–1767.

    CAS  PubMed  Google Scholar 

  49. Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R et al. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blood 2007; 109: 3451–3461.

    CAS  PubMed  Google Scholar 

  50. Chang LW, Payton JE, Yuan W, Ley TJ, Nagarajan R, Stormo GD . Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia. Genome Biol 2008; 9: R38.

    PubMed  PubMed Central  Google Scholar 

  51. Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, Scheijen B et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 2010; 24: 1258–1264.

    CAS  PubMed  Google Scholar 

  52. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377–1380.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang JJ, Bhojwani D, Yang W, Cai X, Stocco G, Crews K et al. Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood 2008; 112: 4178–4183.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kuiper RP, van Leeuwen FN, van der Velden V, van Reijmersdal SV, de Vries J, Keijzers-Vloet STM et al. Ikaros Is a frequently affected hematopoietic differentiation factor in pediatric relapse-prone precursor B-cell acute lymphoblastic leukemia. Blood 2008; 112 (abstract 4144).

  55. Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009; 10: 125–134.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 2009; 106: 9414–9418.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

    CAS  PubMed  Google Scholar 

  58. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

    CAS  PubMed  Google Scholar 

  59. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7: 387–397.

    CAS  PubMed  Google Scholar 

  60. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.

    CAS  PubMed  Google Scholar 

  61. Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 2009; 41: 1243–1246.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Malinge S, Ben-Abdelali R, Settegrana C, Radford-Weiss I, Debre M, Beldjord K et al. Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia. Blood 2007; 109: 2202–2204.

    CAS  PubMed  Google Scholar 

  63. Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 2008; 372: 1484–1492.

    CAS  PubMed  Google Scholar 

  64. Kearney L, Gonzalez De Castro D, Yeung J, Procter J, Horsley SW, Eguchi-Ishimae M et al. A specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukaemia. Blood 2008; 113: 646–648.

    PubMed  Google Scholar 

  65. Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med 2008; 205: 751–758.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S et al. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol 2009; 144: 930–932.

    CAS  PubMed  Google Scholar 

  67. Baker SJ, Rane SG, Reddy EP . Hematopoietic cytokine receptor signaling. Oncogene 2007; 26: 6724–6737.

    CAS  PubMed  Google Scholar 

  68. Ihle JN, Gilliland DG . Jak2: normal function and role in hematopoietic disorders. Curr Opin Genet Dev 2007; 17: 8–14.

    CAS  PubMed  Google Scholar 

  69. Vainchenker W, Dusa A, Constantinescu SN . JAKs in pathology: Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol 2008; 19: 385–393.

    CAS  PubMed  Google Scholar 

  70. Harvey RC, Mullighan CG, Chen IM, Wharton W, Mikhail FM, Carroll AJ et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood 2010; 115: 5312–5321.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood 2009; 114: 2688–2698.

    CAS  PubMed  Google Scholar 

  72. Storlazzi CT, Albano F, Lo Cunsolo C, Doglioni C, Guastadisegni MC, Impera L et al. Upregulation of the SOX5 by promoter swapping with the P2RY8 gene in primary splenic follicular lymphoma. Leukemia 2007; 21: 2221–2225.

    CAS  PubMed  Google Scholar 

  73. Yoda A, Yoda Y, Chiaretti S, Bar-Natan M, Mani K, Rodig SJ et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci USA 2010; 107: 252–257.

    CAS  PubMed  Google Scholar 

  74. Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J et al. Down syndrome acute lymphoblastic leukemia: a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the iBFM Study Group. Blood 2010; 115: 1006–1017.

    CAS  PubMed  Google Scholar 

  75. Chapiro E, Russell L, Lainey E, Kaltenbach S, Ragu C, Della-Valle V et al. Activating mutation in the TSLPR gene in B-cell precursor lymphoblastic leukemia. Leukemia 2010; 24: 642–645.

    CAS  PubMed  Google Scholar 

  76. Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalova K et al. Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. Blood 2008; 111: 1575–1583.

    CAS  PubMed  Google Scholar 

  77. Cario G, Zimmermann M, Romey R, Gesk S, Vater I, Harbott J et al. Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood 2010; 115: 5393–5397.

    CAS  PubMed  Google Scholar 

  78. Pandey A, Ozaki K, Baumann H, Levin SD, Puel A, Farr AG et al. Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nat Immunol 2000; 1: 59–64.

    CAS  PubMed  Google Scholar 

  79. Hiroyama T, Iwama A, Morita Y, Nakamura Y, Shibuya A, Nakauchi H . Molecular cloning and characterization of CRLM-2, a novel type I cytokine receptor preferentially expressed in hematopoietic cells. Biochem Biophys Res Commun 2000; 272: 224–229.

    CAS  PubMed  Google Scholar 

  80. Park LS, Martin U, Garka K, Gliniak B, Di Santo JP, Muller W et al. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med 2000; 192: 659–670.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhang W, Wang J, Wang Q, Chen G, Zhang J, Chen T et al. Identification of a novel type I cytokine receptor CRL2 preferentially expressed by human dendritic cells and activated monocytes. Biochem Biophys Res Commun 2001; 281: 878–883.

    CAS  PubMed  Google Scholar 

  82. Mazzucchelli R, Hixon JA, Spolski R, Chen X, Li WQ, Hall VL et al. Development of regulatory T cells requires IL-7Ralpha stimulation by IL-7 or TSLP. Blood 2008; 112: 3283–3292.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Ziegler SF, Liu YJ . Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol 2006; 7: 709–714.

    CAS  PubMed  Google Scholar 

  84. Al-Shami A, Spolski R, Kelly J, Keane-Myers A, Leonard WJ . A role for TSLP in the development of inflammation in an asthma model. J Exp Med 2005; 202: 829–839.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Rochman Y, Leonard WJ . Thymic stromal lymphopoietin: a new cytokine in asthma. Curr Opin Pharmacol 2008; 8: 249–254.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 2005; 6: 1047–1053.

    CAS  PubMed  Google Scholar 

  87. Ray RJ, Furlonger C, Williams DE, Paige CJ . Characterization of thymic stromal-derived lymphopoietin (TSLP) in murine B cell development in vitro. Eur J Immunol 1996; 26: 10–16.

    CAS  PubMed  Google Scholar 

  88. Vosshenrich CA, Cumano A, Muller W, Di Santo JP, Vieira P . Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proc Natl Acad Sci USA 2004; 101: 11070–11075.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Astrakhan A, Omori M, Nguyen T, Becker-Herman S, Iseki M, Aye T et al. Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development. Nat Immunol 2007; 8: 522–531.

    CAS  PubMed  Google Scholar 

  90. Brown VI, Hulitt J, Fish J, Sheen C, Bruno M, Xu Q et al. Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. Cancer Res 2007; 67: 9963–9970.

    CAS  PubMed  Google Scholar 

  91. Scheeren FA, van Lent AU, Nagasawa M, Weijer K, Spits H, Legrand N et al. Thymic stromal lymphopoietin induces early human B-cell proliferation and differentiation. Eur J Immunol 2010; 40: 955–965.

    CAS  PubMed  Google Scholar 

  92. Carpino N, Thierfelder WE, Chang MS, Saris C, Turner SJ, Ziegler SF et al. Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Mol Cell Biol 2004; 24: 2584–2592.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Pardanani A . JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials. Leukemia 2008; 22: 23–30.

    CAS  PubMed  Google Scholar 

  94. Verstovsek S . Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program 2009, 636–642.

    Google Scholar 

  95. 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 USA 2008; 105: 6708–6713.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Usvasalo A, Elonen E, Saarinen-Pihkala UM, Raty R, Harila-Saari A, Koistinen P et al. Prognostic classification of patients with acute lymphoblastic leukemia by using gene copy number profiles identified from array-based comparative genomic hybridization data. Leukemia Res 2010, e-pub ahead of print 18 March 2010.

  97. Okamoto R, Ogawa S, Nowak D, Kawamata N, Akagi T, Kato M et al. Genomic profiling of adult acute lymphoblastic leukemia (ALL) by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric ALL. Haematologica 2010; e-pub ahead of print 30 April 2010, doi:10.3324/haematol.2009.011114.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Harrison CJ, Moorman AV, Broadfield ZJ, Cheung KL, Harris RL, Reza Jalali G et al. Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. Br J Haematol 2004; 125: 552–559.

    PubMed  Google Scholar 

  99. Heerema NA, Nachman JB, Sather HN, Sensel MG, Lee MK, Hutchinson R et al. Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: a report from the children's cancer group. Blood 1999; 94: 4036–4045.

    CAS  PubMed  Google Scholar 

  100. Pui CH, Williams DL, Raimondi SC, Rivera GK, Look AT, Dodge RK et al. Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Blood 1987; 70: 247–253.

    CAS  PubMed  Google Scholar 

  101. Raimondi SC, Zhou Y, Mathew S, Shurtleff SA, Sandlund JT, Rivera GK et al. Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia. Cancer 2003; 98: 2715–2722.

    PubMed  Google Scholar 

  102. Zhang J, Mullighan CG, Harvey RC, Buetow KE, Carroll WL, Chen I-M et al. Mutations in the RAS signaling, B-cell development, TP53/RB1, and JAK signaling pathways are common in high risk B-precursor childhood acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group (COG) high-risk (HR) ALL TARGET project. Blood 2009; 114: 40 (abstract 85).

    Google Scholar 

  103. Mardis ER, Wilson RK . Cancer genome sequencing: a review. Hum Mol Genet 2009; 18: R163–R168.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008; 456: 66–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361: 1058–1066.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet 2010; 42: 338–342.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 2010; 42: 181–185.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, Jing X et al. Transcriptome sequencing to detect gene fusions in cancer. Nature 2009; 458: 97–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Maher CA, Palanisamy N, Brenner JC, Cao X, Kalyana-Sundaram S, Luo S et al. Chimeric transcript discovery by paired-end transcriptome sequencing. Proc Natl Acad Sci USA 2009; 106: 12353–12358.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Mullighan CG, Morin RD, Zhang J, Hirst M, Zhao Y, Yan C et al. Next generation transcriptomic resequencing identifies novel genetic alterations in high-risk (HR) childhood acute lymphoblastic leukemia (ALL): A report from the Children's Oncology Group (COG) HR ALL TARGET project. Blood 2009; 114: 293 (abstract 704).

    Google Scholar 

Download references

Acknowledgements

We thank colleagues at St Jude Children's Research Hospital and the Children's Oncology Group who have contributed to this work. The studies described here were supported by ALSAC/St Jude and the National Institutes of Health. CGM is supported by the American Society of Hematology and the American Association of Cancer Research, and is a Pew Scholar in the Biomedical Sciences.

Author information

Authors and Affiliations

  1. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA

    J R Collins-Underwood & C G Mullighan

Authors
  1. J R Collins-Underwood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C G Mullighan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C G Mullighan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Collins-Underwood, J., Mullighan, C. Genomic profiling of high-risk acute lymphoblastic leukemia. Leukemia 24, 1676–1685 (2010). https://doi.org/10.1038/leu.2010.177

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.177

Keywords

This article is cited by

Search

Advanced search

Quick links