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Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study

Leukemia volume 15, pages 1442–1447 (2001)Cite this article

Abstract

TEL/AML1 gene fusion that results from a cryptic t(12;21) is the most common genetic aberration in childhood B-lineage acute lymphoblastic leukemia (ALL). While the translocation may initiate the leukemic process, critical secondary genetic events are currently believed to be pivotal for leukemogenesis. We investigated 12 cases of childhood ALL with TEL/AML1 gene fusion by fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) and documented additional or secondary genetic changes in seven patients (58%). Three patients showed extra copies of chromosome 21 including a case in which the trisomy 21 (+21) clone was distinct from the one harboring TEL/AML1 gene fusion. Interestingly, one patient without +21 showed amplification of the AML1 gene on chromosome 21q, supporting the contention that AML1 amplification may be an important additional genetic event. Gene expression study by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) in two of these four patients showed an increase in AML1 transcripts that paralleled the increase in gene copy number. Deletion of the normal TEL allele was detected in two patients, with one of them showing loss of chromosome 12 together with duplication of the der(12)t(12;21). Finally, one patient showed duplication of the fusion signal. Our findings confirm that additional or secondary genetic changes including AML1 amplification are commonly encountered in childhood ALL with TEL/AML1 gene fusion, which are envisaged to play significant roles in disease progression.

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References

  1. Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P, Morgan E, Raimondi SC, Rowley JD, Gilliland DG . Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia Proc Natl Acad Sci USA 1995 92: 4917–4921

    Article  CAS  Google Scholar 

  2. Romana SP, Mauchauffé M, Le Coniat M, Chumakov I, Le Paslier D, Berger R, Bernard OA . The t(12;21) of acute lymphoblastic leukemia results in tel-AML1 gene fusion Blood 1995 85: 3662–3670

    CAS  PubMed  Google Scholar 

  3. Shurtleff SA, Buijs A, Behm FG, Rubnitz JE, Raimondi SC, Hancock ML, Chan GC-F, Pui C-H, Grosveld G, Downing JR . TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis Leukemia 1995 9: 1985–1989

    CAS  PubMed  Google Scholar 

  4. Fears S, Vignon C, Bohlander SK, Smith S, Rowley JD, Nucifora G . Correlation between the ETV6/CBFA2 (TEL/AML1) fusion gene and karyotypic abnormalities in children with B-cell precursor acute lymphoblastic leukemia Genes Chromos Cancer 1996 17: 127–135

    Article  CAS  Google Scholar 

  5. Romana SP, Poirel H, Leconiat M, Flexor M-A, Mauchauffé M, Jonveaux P, Macintyre EA, Berger R, Bernard OA . High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia Blood 1995 86: 4263–4269

    CAS  PubMed  Google Scholar 

  6. McLean TW, Ringold S, Neuberg D, Stegmaier K, Tantravahi R, Ritz J, Koeffler HP, Takeuchi S, Janssen JWG, Seiru T, Bartram CR, Sallan SE, Gilliland DG, Golub TR . TEL/AML1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia Blood 1996 88: 4252–4258

    CAS  PubMed  Google Scholar 

  7. Raynaud S, Cavé H, Beans M, Bastard S, Cacheux V, Grosgeorge J, Guidal-Giroux C, Guo C, Vilmer E, Marynen P, Grandchamp B . The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia Blood 1996 87: 2891–2899

    CAS  PubMed  Google Scholar 

  8. Borkhardt A, Cazzaniga G, Viehmann S, Valsecchi MG, Ludwig WD, Burci L, Mangioni S, Schrappe M, Riehm H, Lampert F, Basso G, Masera G, Harbott J, Biondi A . Incidence and clinical relevance of TEL/AML1 fusion gene 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

    CAS  PubMed  Google Scholar 

  9. Loh ML, McLean TW, Buckley JD, Howells W, Gilliland DG, Smith FO . Lack of TEL/AML1 fusion in pediatric AML: further evidence for lineage specificity of TEL/AML1 Leuk Res 1998 22: 461–464

    Article  CAS  Google Scholar 

  10. Aguiar RC, Sohal J, van Rhee F, Carapeti M, Franklin IM, Goldstone AH, Goldman JM, Cross NC . TEL-AML1 fusion in acute lymphoblastic leukaemia of adults. MRC Adult Leukaemia Working Party Br J Haematol 1996 95: 673–677

    Article  CAS  Google Scholar 

  11. Hiebert SW, Sun W, Davis N, Golub T, Shurtleff S, Buijs A, Downing JR, Grosveld G, Roussel MF, Gilliland DG, Lenny N, Meyers S . The t(12;21) translocation converts AML-1B froma an activator to a repressor of transcription Mol Cell Biol 1996 16: 1349–1355

    Article  CAS  Google Scholar 

  12. Rubnitz JE, Downing JR, Pui C-H, Shurtleff SA, Raimondi SC, Evans WE, Head DR, Crist WM, Rivera GK, Hancock ML, Boyett JM, Buijs A, Grosveld G, Behm FG . TEL gene rearrangement in acute lymphoblastic leukemia: a new genetic marker with prognostic significance J Clin Oncol 1997 15: 1150–1157

    Article  CAS  Google Scholar 

  13. Harbott J, Viehmann S, Borkhardt A, Henze G, Lampert F . Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse Blood 1997 90: 4933–4937

    CAS  PubMed  Google Scholar 

  14. Seeger K, Adams H-P, Buchwald D, Beyermann B, Kremens B, Niemeyer C, Ritter J, Schwabe D, Harms D, Schrappe M, Henze G . TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin–Frankfurt–Münster Study Group Blood 1998 91: 1716–1722

    CAS  PubMed  Google Scholar 

  15. Loh ML, Silverman LB, Young ML, Neuberg D, Golub TR, Sallan SE, Gilliland DG . Incidence of TEL/AML1 fusion in children with relapsed acute lymphoblastic leukemia Blood 1998 92: 4792–4797

    CAS  PubMed  Google Scholar 

  16. Rubnitz JE, Behm FG, Wichlan D, Ryan C, Sandlund JT, Ribeiro RC, Rivera GK, Hancock ML, Relling MV, Evans WE, Pui CH, Downing JR . Low frequency of TEL-AML1 in relapsed acute lymphoblastic leukemia supports a favorable prognosis for this genetic subgroup Leukemia 1999 13: 19–21

    Article  CAS  Google Scholar 

  17. Zuna J, Hrisak O, Kalinova M, Muzikova K, Stary L, Trka J . TEL/AML1 positivity in childhood ALL: average or better prognosis? Czech Paediatric Haematology Working Group Leukemia 1999 13: 22–24

    Article  CAS  Google Scholar 

  18. Takahashi Y, Horibe K, Kiyoi H, Miyashita Y, Fukuda M, Mori H, Nozaki C, Hasegawa S, Kawabe T, Kato K, Kojima S, Matuyama T, Naoe T . Prognostic significance of TEL/AML1 fusion transcript in childhood B-precursor acute lymphoblastic leukemia J Pediatr Hematol Oncol 1998 20: 190–195

    Article  CAS  Google Scholar 

  19. Avigad S, Kuperstein G, Zilberstein J, Liberzon E, Stark B, Gelernter I, Kodman Y, Luria D, Ash S, Stein J, Goshen Y, Yaniv I, Cohen IJ, Zaizov R . TEL-AML1 fusion transcript designates a favorable outcome with an intensified protocol in childhood acute lymphoblastic leukemia Leukemia 1999 13: 481–483

    Article  CAS  Google Scholar 

  20. Ford AM, Bennett CA, Price CM, Bruin MC, Van Wering ER, Greaves M . Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia Proc Natl Acad Sci USA 1998 95: 4584–4588

    Article  CAS  Google Scholar 

  21. Wiemels JL, Cazzaniga G, Daniotti M, Eden OB, Addison GM, Masera G, Saha V, Biondi A, Greaves MF . Prenatal origin of acute lymphoblastic leukaemia in children Lancet 1999 354: 1499–1503

    Article  CAS  Google Scholar 

  22. Greaves M . A natural history for pediatric acute leukemia Blood 1993 82: 1043–1051

    CAS  PubMed  Google Scholar 

  23. Wiemels JL, Ford AM, Van Wering ER, Postma A, Greaves M . Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero Blood 1999 94: 1057–1062

    CAS  PubMed  Google Scholar 

  24. Raynaud SD, Dastugue N, Zoccola D, Shurtleff SA, Mathew S, Raimondi SC . Cytogenetic abnormalities associated with the t(12;21): a collaborative study of 169 children with t(12;21)-positive acute lymphoblastic leukemia Leukemia 1999 13: 1325–1330

    Article  CAS  Google Scholar 

  25. Kwong YL, Wong KF . Low frequency of TEL/AML1 in adult acute lymphoblastic leukemia Cancer Genet Cytogenet 1997 98: 137–138

    Article  CAS  Google Scholar 

  26. Ma SK, Ha SY, Chan GCF, Ching LM, Lau YL, Chan LC . Cytogenetic abnormalities in pediatric myelodysplastic syndrome: a report of three cases Cancer Genet Cytogenet 1997 93: 172–176

    Article  CAS  Google Scholar 

  27. Kalliomiemi A, Kalliomiemi O-P, Suder D, Rutoritz D, Gray JW, Waldman F, Pinkel D . Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors Science 1992 258: 818–821

    Article  Google Scholar 

  28. Miyoshi H, Ohira M, Shimizu K, Mitani K, Hirai H, Imai T, Yokoyama K, Soeda E, Ohki M . Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia Nucleic Acids Res 1995 23: 2762–2769

    Article  CAS  Google Scholar 

  29. Cavé H, Cacheux V, Raynaud S, Brunie G, Bakkus M, Cochaux P, Preudhomme C, Laï JL, Vilmer E, Grandchamp B . ETV6 is the target of chromosome 12p deletions in t(12;21) childhood acute lymphoblastic leukemia Leukemia 1997 11: 1459–1464

    Article  Google Scholar 

  30. Raimondi SC, Shurtleff SA, Downing JR, Rubnitz J, Mathew S, Hancock M, Pui C-H, Rivera GK, Grosveld GC, Behm FG . 12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia Blood 1997 90: 4559–4566

    CAS  PubMed  Google Scholar 

  31. Takeuchi S, Seriu T, Bartram CR, Golub TR, Reiter A, Miyoshi I, Gilliland DG, Koeffler HP . TEL is one of the targets for deletion on 12p in many cases of childhood B-lineage acute lymphoblastic leukemia Leukemia 1997 11: 1220–1223

    Article  CAS  Google Scholar 

  32. Ma SK, Wan TSK, Chan LC . Cytogenetics and molecular genetics of childhood leukemia Hematol Oncol 1999 17: 91–105

    Article  CAS  Google Scholar 

  33. Niini T, Kanerva J, Vettenranta K, Saarinen-Pihkala UM, Knuutila S . AML1 gene amplification: a novel finding in childhood acute lymphoblastic leukemia Haematologica 2000 85: 362–366

    CAS  PubMed  Google Scholar 

  34. Loncarevic IF, Roitzheim B, Ritterbach J, Viehmann S, Borkhardt A, Lampert F, Harbott J . Trisomy 21 is a recurrent secondary aberration in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion Genes Chromos Cancer 1999 24: 272–277

    Article  CAS  Google Scholar 

  35. Andreasson P, Johansson B, Strömbeck B, Donnër •, Mitelman F, Höglund M . Childhood acute lymphoblastic leukemia with ider(21)(q10)t(12;21)(p12;q22): a new recurrent abnormality showing ETV6/CBFA2 fusion Br J Haematol 1997 98: 216–218

    Article  CAS  Google Scholar 

  36. Kobayashi H, Satake N, Maseki N, Sakashita A, Kaneko Y . The der(21)t(12;21) chromosome is always formed in a 12;21 translocation associated with childhood acute lymphoblastic leukemia Br J Haematol 1996 94: 105–111

    Article  CAS  Google Scholar 

  37. Lanza C, Volpe G, Basso G, Gottardi E, Perfetto F, Cilli V, Spinelli M, Ricotti E, Guerrasio A, Madon E, Saglio G . The common TEL/AML1 rearrangement does not represent a frequent event in acute lymphoblastic leukemia occurring in children with Down syndrome Leukemia 1997 11: 820–821

    Article  CAS  Google Scholar 

  38. Najfeld V, Lai J, Scalise A, Guarini L, Lipton JM . Amplification of q22 chromosomal region of chromosome 21, including AML-1 gene, is a clonal marker in pediatric patients with acute lymphoblastic leukemia (ALL) Blood 1998 92: (Suppl 1) 396a

    Google Scholar 

  39. Heerema NA, Stork L, Crotty ML, Ceperich TM, Sarquis M, Yanofsky R, Gaynon PS, Sather HN, Uckun FM . TEL-AML1 expression in childhood acute lymphoblastic leukemia (ALL) is associated with rapid early response (RER) to induction chemotherapy Blood 1999 94: (Suppl. 1) 502a

    Google Scholar 

  40. Fenrick R, Amann JM, Lutterbach B, Wang L, Westendorf JJ, Downing JR, Hiebert SW . Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein Mol Cell Biol 1999 19: 6566–6574

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China

    SK Ma, TSK Wan, ATC Cheuk, LF Fung & LC Chan

  2. Department of Pediatrics, The University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China

    GCF Chan, SY Chan & SY Ha

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Ma, S., Wan, T., Cheuk, A. et al. Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study. Leukemia 15, 1442–1447 (2001). https://doi.org/10.1038/sj.leu.2402202

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