Seminars in Diagnostic Pathology
Volume 29, Issue 1 , Pages 2-11 , February 2012

Beyond the 2008 World Health Organization classification: the role of the hematopathology laboratory in the diagnosis and management of acute lymphoblastic leukemia

  • Stephanie McGregor, MD, PhD

      Affiliations

    • Department of Pathology, University of Chicago, Chicago, Illinois
  • ,
  • Jennifer McNeer, MD, MS

      Affiliations

    • Department of Pediatrics, University of Chicago, Chicago, Illinois
  • ,
  • Sandeep Gurbuxani, MBBS, PhD

      Affiliations

    • Department of Pathology, University of Chicago, Chicago, Illinois
    • Corresponding Author InformationAddress reprint requests and correspondence: Sandeep Gurbuxani, MBBS, PhD, Department of Pathology, University of Chicago, Chicago, IL 60637

References 

  1. Pui CH , Carroll WL , Meshinchi S , et al.  Biology, risk stratification, and therapy of pediatric acute leukemias: an update . J Clin Oncol . 2011;29:551–565
  2. Smith M , Arthur D , Camitta B , et al.  Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia . J Clin Oncol . 1996;14:18–24
  3. Look AT , Roberson PK , Williams DL , et al.  Prognostic importance of blast cell DNA content in childhood acute lymphoblastic leukemia . Blood . 1985;65:1079–1086
  4. Moorman AV , Ensor HM , Richards SM , et al.  Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial . Lancet Oncol . 2010;11:429–438
  5. Trueworthy R , Shuster J , Look T , et al.  Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: a Pediatric Oncology Group study . J Clin Oncol . 1992;10:606–613
  6. Harris MB , Shuster JJ , Carroll A , et al.  Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study . Blood . 1992;79:3316–3324
  7. Sutcliffe MJ , Shuster JJ , Sather HN , et al.  High concordance from independent studies by the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG) associating favorable prognosis with combined trisomies 4, 10, and 17 in children with NCI Standard-Risk B-precursor Acute Lymphoblastic Leukemia: a Children's Oncology Group (COG) initiative . Leukemia . 2005;19:734–740
  8. Heerema NA , Sather HN , Sensel MG , et al.  Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes) . J Clin Oncol . 2000;18:1876–1887
  9. Borkhardt A , Cazzaniga G , Viehmann S , et al.  Incidence and clinical relevance of TEL/AML1 fusion genes in children with acute lymphoblastic leukemia enrolled in the German and Italian multicenter therapy trials (Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Study Group) . Blood . 1997;90:571–577
  10. McLean TW , Ringold S , Neuberg D , et al.  TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia . Blood . 1996;88:4252–4258
  11. Rubnitz JE , Downing JR , Pui CH , et al.  TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance . J Clin Oncol . 1997;15:1150–1157
  12. Borowitz MJ , Devidas M , Hunger SP , et al.  Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study . Blood . 2008;111:5477–5485
  13. Chessels JM , Swansbury GJ , Reeves B , et al.  Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X (Medical Research Council Working Party in Childhood Leukaemia) . Br J Haematol . 1997;99:93–100
  14. Nachman JB , Heerema NA , Sather H , et al.  Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia . Blood . 2007;110:1112–1115
  15. Harrison CJ , Haas O , Harbott J , et al.  Detection of prognostically relevant genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: recommendations from the Biology and Diagnosis Committee of the International Berlin-Frankfürt-Münster study group . Br J Haematol . 2010;151:132–142
  16. Aricò M , Valsecchi MG , Camitta B , et al.  Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia . N Engl J Med . 2000;342:998–1006
  17. Uckun FM , Nachman JB , Sather HN , et al.  Poor treatment outcome of Philadelphia chromosome-positive pediatric acute lymphoblastic leukemia despite intensive chemotherapy . Leuk Lymphoma . 1999;33:101–106
  18. Schultz KR , Bowman WP , Aledo A , et al.  Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a Children's Oncology Group study . J Clin Oncol . 2009;27:5175–5181
  19. Crist WM , Carroll AJ , Shuster JJ , et al.  Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study . Blood . 1990;76:117–122
  20. Raimondi SC , Behm FG , Roberson PK , et al.  Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19) . J Clin Oncol . 1990;8:1380–1388
  21. Felice MS , Gallego MS , Alonso CN , et al.  Prognostic impact of t(1;19)/TCF3-PBX1 in childhood acute lymphoblastic leukemia in the context of Berlin-Frankfurt-Münster-based protocols . Leuk Lymphoma . 2011;52:1215–1221
  22. Robinson HM , Broadfield ZJ , Cheung KL , et al.  Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome . Leukemia . 2003;17:2249–2250
  23. Moorman AV , Richards SM , Robinson HM , et al.  Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21) . Blood . 2007;109:2327–2330
  24. Attarbaschi A , Mann G , Panzer-Grümayer R , et al.  Minimal residual disease values discriminate between low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and an intrachromosomal amplification of chromosome 21: the Austrian and German acute lymphoblastic leukemia Berlin-Frankfurt-Munster (ALL-BFM) trials . J Clin Oncol . 2008;26:3046–3050
  25. Hunger SP . Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia: clinical features and molecular pathogenesis . Blood . 1996;87:1211–1224
  26. Inukai T , Hirose K , Inaba T , et al.  Hypercalcemia in childhood acute lymphoblastic leukemia: frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19 . Leukemia . 2007;21:288–296
  27. Graux C , Cools J , Michaux L , et al.  Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast . Leukemia . 2006;20:1496–1510
  28. Bassan R , Hoelzer D . Modern therapy of acute lymphoblastic leukemia . J Clin Oncol . 2011;29:532–543
  29. Campana D . Minimal residual disease in acute lymphoblastic leukemia . Hematol Am Soc Hematol Educ Programs . 2010;2010:7–12
  30. den Boer ML , van Slegtenhorst M , de Menezes RX , et al.  A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study . Lancet Oncol . 2009;10:125–134
  31. Mullighan CG , Su X , Zhang J , et al.  Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia . N Engl J Med . 2009;360:470–480
  32. Mullighan CG , Miller CB , Radtke I , et al.  BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros . Nature . 2008;453:110–114
  33. Mullighan CG , Zhang J , Harvey RC , et al.  JAK mutations in high-risk childhood acute lymphoblastic leukemia . Proc Natl Acad Sci U S A . 2009;106:9414–9418
  34. Mullighan CG , Collins-Underwood JR , Phillips LAA , et al.  Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia . Nat Genet . 2009;41:1243–1246
  35. Cario G , Zimmermann M , Romey R , 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
  36. Harvey RC , Mullighan CG , Wang X , et al.  Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome . Blood . 2010;116:4874–4884
  37. Pardanani A . JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials . Leukemia . 2008;22:23–30
  38. Kuiper RP , Schoenmakers EFPM , van Reijmersdal SV , 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
  39. Mullighan CG , Goorha S , Radtke I , et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia . Nature . 2007;446:758–764
  40. Iacobucci I , Lonetti A , Paoloni F , et al.  The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome (A report on behalf of the GIMEMA Acute Leukemia Working Party) . Haematologica . 2010;95:1683–1690
  41. Pullen J , Shuster JJ , Link M , et al.  Significance of commonly used prognostic factors differs for children with T cell acute lymphocytic leukemia (ALL), as compared to those with B-precursor ALL (A Pediatric Oncology Group (POG) study) . Leukemia . 1999;13:1696–1707
  42. Pui CH , Behm FG , Crist WM . Clinical and biologic relevance of immunologic marker studies in childhood acute lymphoblastic leukemia . Blood . 1993;82:343–362
  43. Uckun FM , Gaynon PS , Sensel MG , et al.  Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study . J Clin Oncol . 1997;15:2214–2221
  44. van Grotel M , Meijerink JPP , van Wering ER , et al.  Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences . Leukemia . 2008;22:124–131
  45. Cavé H , Suciu S , Preudhomme C , et al.  Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951 . Blood . 2004;103:442–450
  46. Ferrando AA , Neuberg DS , Staunton J , et al.  Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia . Cancer Cell . 2002;1:75–87
  47. Ferrando AA , Neuberg DS , Dodge RK , et al.  Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia . Lancet . 2004;363:535–536
  48. Haferlach T , Kohlmann A , Wieczorek L , et al.  Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group . J Clin Oncol . 2010;28:2529–2537
  49. Cleaver AL , Beesley AH , Firth MJ , et al.  Gene-based outcome prediction in multiple cohorts of pediatric T-cell acute lymphoblastic leukemia: a Children's Oncology Group study . Mol Cancer . 2010;9:105
  50. Ellisen LW , Bird J , West DC , et al.  TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms . Cell . 1991;66:649–661
  51. Ma SK , Wan TS , Chan LC . Cytogenetics and molecular genetics of childhood leukemia . Hematol Oncol . 1999;17:91–105
  52. Weng AP , Ferrando AA , Lee W , et al.  Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia . Science . 2004;306:269–271
  53. Palomero T , Dominguez M , Ferrando AA . The role of the PTEN/AKT pathway in NOTCH1-induced leukemia . Cell Cycle . 2008;7:965–970
  54. Aifantis I , Vilimas T , Buonamici S . Notches, NFkappaBs and the making of T cell leukemia . Cell Cycle . 2007;6:403–406
  55. Demarest RM , Ratti F , Capobianco AJ . It's T-ALL about Notch . Oncogene . 2008;27:5082–5091
  56. Palomero T , Sulis ML , Cortina M , et al.  Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia . Nat Med . 2007;13:1203–1210
  57. Silva A , Yunes JA , Cardoso BA , et al.  PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability . J Clin Invest . 2008;118:3762–3774
  58. Asnafi V , Buzyn A , Le Noir S , et al.  NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study . Blood . 2009;113:3918–3924
  59. Breit S , Stanulla M , Flohr T , et al.  Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia . Blood . 2006;108:1151–1157
  60. Malyukova A , Dohda T , von der Lehr N , et al.  The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling . Cancer Res . 2007;67:5611–5616
  61. Park MJ , Taki T , Oda M , et al.  FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma . Br J Haematol . 2009;145:198–206
  62. Baldus CD , Thibaut J , Goekbuget N , et al.  Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia . Haematologica . 2009;94:1383–1390
  63. Zuurbier L , Homminga I , Calvert V , et al.  NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols . Leukemia . 2010;24:2014–2022
  64. Clappier E , Collette S , Grardel N , et al.  NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951 . Leukemia . 2010;24:2023–2031
  65. Mansour MR , Sulis ML , Duke V , et al.  Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol . J Clin Oncol . 2009;27:4352–4356
  66. Larson Gedman A , Chen Q , Kugel Desmoulin S , et al.  The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group . Leukemia . 2009;23:1417–1425
  67. Palomero T , Ferrando A . Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia . Clin Lymphoma Myeloma 9 suppl . 2009;3:S205–S210
  68. Milano J , McKay J , Dagenais C , et al.  Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation . Toxicol Sci . 2004;82:341–358
  69. van Es JH , van Gijn ME , Riccio O , et al.  Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells . Nature . 2005;435:959–963
  70. Wei P , Walls M , Qiu M , et al.  Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design . Mol Cancer Ther . 2010;9:1618–1628
  71. Real PJ , Tosello V , Palomero T , et al.  Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia . Nat Med . 2009;15:50–58
  72. Real PJ , Ferrando AA . NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia . Leukemia . 2009;23:1374–1377
  73. Coustan-Smith E , Mullighan CG , Onciu M , et al.  Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia . Lancet Oncol . 2009;10:147–156
  74. Gutierrez A , Dahlberg SE , Neuberg DS , et al.  Absence of biallelic TCRgamma deletion predicts early treatment failure in pediatric T-cell acute lymphoblastic leukemia . J Clin Oncol . 2010;28:3816–3823
  75. Stumpel DJPM , Schneider P , van Roon EHJ , et al.  Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options . Blood . 2009;114:5490–5498
  76. Román-Gómez J , Jiménez-Velasco A , Agirre X , et al.  CpG island methylator phenotype redefines the prognostic effect of t(12;21) in childhood acute lymphoblastic leukemia . Clin Cancer Res . 2006;12:4845–4850
  77. Román-Gómez J , Jiménez-Velasco A , Agirre X , et al.  Lack of CpG island methylator phenotype defines a clinical subtype of T-cell acute lymphoblastic leukemia associated with good prognosis . J Clin Oncol . 2005;23:7043–7049
  78. Román-Gómez J , Jiménez-Velasco A , Castillejo JA , et al.  Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia . Blood . 2004;104:2492–2498
  79. Milani L , Lundmark A , Kiialainen A , et al.  DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia . Blood . 2010;115:1214–1225
  80. Mullighan CG , Zhang J , Kasper LH , et al.  CREBBP mutations in relapsed acute lymphoblastic leukaemia . Nature . 2011;471:235–239
  81. Stumpel DJPM , Schotte D , Lange-Turenhout EAM , et al.  Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale . Leukemia . 2011;25:429–439
  82. Román-Gómez J , Agirre X , Jiménez-Velasco A , et al.  Epigenetic regulation of microRNAs in acute lymphoblastic leukemia . J Clin Oncol . 2009;27:1316–1322
  83. Román-Gómez J , Cordeu L , Agirre X , et al.  Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia . Blood . 2007;109:3462–3469
  84. Ruiz-Magaña MJ , Rodríguez-Vargas JM , Morales JC , et al.  The DNA-methyltransferase inhibitors zebularine and decitabine induce mitochondria-mediated apoptosis and DNA damage in p53 mutant leukemic T cells . Int J Cancer . 2011; epub ahead of print 31 March
  85. Okamoto R , Ogawa S , Nowak D , et al.  Genomic profiling of adult acute lymphoblastic leukemia by single nucleotide polymorphism oligonucleotide microarray and comparison to pediatric acute lymphoblastic leukemia . Haematologica . 2010;95:1481–1488
  86. Paulsson K , Cazier JB , Macdougall F , 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
  87. Yoda A , Yoda Y , Chiaretti S , et al.  Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia . Proc Natl Acad Sci U S A . 2010;107:252–257
  88. Harvey RC , Mullighan CG , Chen IM , 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
  89. O'Neil J , Grim J , Strack P , et al.  FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors . J Exp Med . 2007;204:1813–1824
  90. Thompson BJ , Buonamici S , Sulis ML , et al.  The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia . J Exp Med . 2007;204:1825–1835

PII: S0740-2570(11)00098-0

doi: 10.1053/j.semdp.2011.07.004

Seminars in Diagnostic Pathology
Volume 29, Issue 1 , Pages 2-11 , February 2012