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Cryptic insertion and translocation or nondividing leukemic cells disclosed by FISH analysis in infant acute leukemia with discrepant molecular and cytogenetic findings

Abstract

Of 51 infants with acute leukemia, 13 (25%) had contradictory findings on 11q23/MLL rearrangements that were analyzed by cytogenetic and Southern blot methods: seven had rearranged MLL and normal karyotype, four had rearranged MLL and abnormal karyotype with no 11q23 translocation, and two had germline MLL and 11q23 translocations. Fluorescent in situ hybridization (FISH) analysis using an MLL probe that was performed to elucidate the discrepancy disclosed the presence of normal dividing cells and nondividing leukemic cells in the same bone marrow in five patients, and cryptic insertion or translocation in another five. Subsequent FISH and reverse transcription-polymerase chain reaction analysis identified the MLL–AF10, MLL–AF4, or MLL–AF1q fusions that were produced by the cryptic rearrangements in four of the five patients. In the remaining three patients, the breakpoint of 11q23 translocation was located distal to the MLL locus in one, and the discrepancy was unresolved in two. Thus, FISH should complement cytogenetic analysis when cytogenetic and molecular genetic findings are contradictory in infant leukemia, and when infant leukemia does not show 11q23 translocations or other specific translocations including t(7;12), t(1;22), etc that are recurrently found in infant leukemia.

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References

  1. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  2. Maseki N, Miyoshi H, Shimizu K, Homma C, Ohki M, Sakurai M et al. The 8;21 chromosome translocation in acute myeloid leukemia is always detectable by molecular analysis using AML1. Blood 1993; 81: 1573–1579.

    CAS  PubMed  Google Scholar 

  3. Bower M, Parry P, Carter M, Lillington DM, Amess J, Lister TA et al. Prevalence and clinical correlations of MLL gene rearrangements in AML-M4/5. Blood 1994; 84: 3776–3780.

    CAS  PubMed  Google Scholar 

  4. Rubnitz JE, Link MP, Shuster JJ, Carroll AJ, Hakami N, Frankel LS et al. Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a pediatric oncology group study. Blood 1994; 84: 570–573.

    CAS  PubMed  Google Scholar 

  5. Grimwade D, Gorman P, Duprez E, Howe K, Langebeer S, Oliver F et al. Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. Blood 1997; 90: 4876–4885.

    CAS  PubMed  Google Scholar 

  6. Satake N, Maseki N, Nishiyama M, Kobayashi H, Sakurai M, Inaba H et al. Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants. Leukemia 1999; 13: 1013–1017.

    Article  CAS  PubMed  Google Scholar 

  7. Huret JL . An atlas on chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia 2001; 15: 987–999.

    Article  CAS  PubMed  Google Scholar 

  8. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative group. Ann Intern Med 1985; 103: 626–629.

    Article  Google Scholar 

  9. ISCN. In: Mitelman F (ed). An International System for Human Cytogenetic Nomenclature. Basel: Karger, 1995.

  10. Yamamoto K, Seto M, Komatsu H, Iida S, Akao Y, Kojima S et al. Two distinct portions of LTG19/ENL are involved in t(11;19) leukemia. Oncogene 1993; 8: 2617–2625.

    CAS  PubMed  Google Scholar 

  11. Nilson I, Lochner K, Siegler G, Greil J, Beck JD, Fey GH et al. Exon/intron structure of the human ALL-1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias. Br J Haematol 1996; 93: 966–972.

    Article  CAS  PubMed  Google Scholar 

  12. Kobayashi H, Satake N, Maseki N, Sakashita A, Kaneko Y . The der(12)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  PubMed  Google Scholar 

  13. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 1987; 162: 156–159.

    Article  CAS  PubMed  Google Scholar 

  14. Uckun FM, Hatten KH, Crotty ML, Sensel MG, Sather HN, Ahlgren LT et al. Clinical significance of MLL–AF4 fusion transcript expression in the absence of a cytogenetically detectable t(4;11)(q21;q23) chromosomal translocation. Blood 1998; 92: 810–821.

    CAS  PubMed  Google Scholar 

  15. Tse W, Zhu W, Chen HS, Cohen A . A novel gene, AF1q, fused to MLL in t(1;11)(q21;q23), is specifically expressed in leukemia and immature hematopoietic cells. Blood 1995; 85: 650–656.

    CAS  PubMed  Google Scholar 

  16. Chaplin T, Ayton P, Bernard OA, Saha V, Valle VD, Hillion J et al. A novel class of zinc finger/leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia. Blood 1995; 85: 1435–1441.

    CAS  PubMed  Google Scholar 

  17. Andersson A, Hoglund M, Johansson B, Lassen C, Billstrom R, Garwicz S et al. Paired multiplex reverse-transcriptase polymerase chain reaction (PMRT-PCR) analysis as a rapid and accurate diagnostic tool for the detection of MLL fusion genes in hematologic malignancies. Leukemia 2001; 15: 1293–1300.

    Article  CAS  PubMed  Google Scholar 

  18. Schichman SA, Caligiuri MA, Gu Y, Strout MP, Canaani E, Bloomfield CD et al. ALL-1 partial duplication in acute leukemia. Proc Natl Acad Sci USA 1994; 91: 6236–6239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Borkhardt A, Wuchter C, Viehmann S, Pils S, Teigler-Schlegel A, Stanulla M et al. Infant acute lymphoblastic leukemia – combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Leukemia 2002; 16: 1685–1690.

    Article  CAS  PubMed  Google Scholar 

  20. Hagemeijer A, Buijs A, Smit E, Janssen B, Creemers GJ, Plas DV et al. Translocation of BCR to chromosome 9: a new cytogenetic variant detected by FISH in two Ph-negative, BCR-positive patients with chronic myeloid leukemia. Genes Chromosomes Cancer 1993; 8: 237–245.

    Article  CAS  PubMed  Google Scholar 

  21. Kaneko Y, Kobayashi H, Handa M, Satake N, Maseki N. EWS–ERG fusion transcript produced by chromosomal insertion in a Ewing sarcoma. Genes Chromosomes Cancer 1997; 18: 228–231.

    Article  CAS  PubMed  Google Scholar 

  22. Andreasson P, Johansson B, Carlsson M, Jarlsfelt I, Fioretos T, Mitelman F et al. BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion. Genes Chromosomes Cancer 1997; 20: 299–304.

    Article  CAS  PubMed  Google Scholar 

  23. Taviaux S, Brunel V, Dupont M, Fernandez F, Ferraz C, Carbuccia N et al. Simple variant t(8;21) acute myeloid leukemias harbor insertions of the AML1 or ETO genes. Genes Chromosomes Cancer 1999; 24: 165–171.

    Article  CAS  PubMed  Google Scholar 

  24. Von Bergh A, Gargallo P, Prijck B, Vranckx H, Marschalek R, Larripa I et al. Cryptic t(4;11) encoding MLL–AF4 due to insertion of 5′ MLL sequences in chromosome 4. Leukemia 2001; 15: 595–600.

    Article  CAS  PubMed  Google Scholar 

  25. Van Limbergen H, Poppe B, Janssens A, Bock R, Paepe A, Noens L et al. Molecular cytogenetic analysis of 10;11 rearrangements in acute myeloid leukemia. Leukemia 2002; 16: 344–351.

    Article  CAS  PubMed  Google Scholar 

  26. Greaves M . Childhood leukaemia. BMJ 2002; 324: 283–287.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Super HJG, Rothberg PG, Kobayashi H, Freeman AI, Diaz MO, Rowley JD . Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23. Blood 1994; 83: 641–644.

    CAS  Google Scholar 

  28. Ford AM, Bennett CA, Price CM, Bruin MCA, 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  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Welfare and Labor of Japan. We thank Dr M Seto for providing MLL cDNA probes, probe X and pSPR25-1, and Drs Y Arai and M Ohki, National Cancer Center Research Institute in Japan for providing a BAC probe (Rp11-177-h22).

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Watanabe, N., Kobayashi, H., Ichiji, O. et al. Cryptic insertion and translocation or nondividing leukemic cells disclosed by FISH analysis in infant acute leukemia with discrepant molecular and cytogenetic findings. Leukemia 17, 876–882 (2003). https://doi.org/10.1038/sj.leu.2402900

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