Recurrence of Acute Myelogenous Leukemia with the SameAML1/ETO Breakpoint as at Diagnosis after Complete Remission Lasting 15 Years: Analysis of Stored Bone Marrow Smears

Abstract

TheAML1/ETO fusion gene is expressed in virtually all patients with t(8;21)(q22;q22) acute myelogenous leukemia (AML). Long-term complete remission (CR) of AML with t(8;21) has been observed despite the presence of residualAML1/ ETO fusion transcripts, although detection may depend on the sensitivity of the methods used.We examined a patient with recurrent AML who showed the t(8;21)(q22;q22) chromosomal abnormality following a CR of 15 years.The blast cells at the time of recurrence expressed theAML1/ETO fusion transcript, and the breakpoint of theAML1 gene was located on intron 5. Southern blot analysis of the DNA extracted from bone marrow slides that had been made and stored for 15 years revealed the same rearrangement pattern of theAML1 gene. Furthermore, the junction sequences between theAML1 and theETO genes, analyzed by long-distance inverse polymerase chain reaction, proved to be completely identical. These findings can be interpreted in two ways: (1) The initial leukemia clone persisted and finally relapsed after 15 years in the dormant state. (2) AML developed in different subclones having the sameAML1/ETO junctional sequences but with additional genetic changes (second hit).

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References

  1. 1.

    Swirsky DM, Li YS, Matthews JG, Flemans RL, Rees JKH, Hayhoe FGJ. 8;21 translocation in acute granulocytic leukemia: cytological, cytochemical and clinical features.Br J Haematol. 1984;56:199–213.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Berger R, Flandrin G, Bernheim A, et al. Cytogenetic studies on 519 consecutive de novo acute nonlymphocytic leukemias.Cancer Genet Cytogenet. 1987;29:9–21.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Nicifora G, Larson RA, Rowley JD. Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in longterm remission.Blood. 1993;82:712–715.

    Google Scholar 

  4. 4.

    Downing JR, Head JR, Curcio-Brint AM, et al. An AML1/ETO fusion transcript is consistently detected by RNA-based polymerase chain reaction in acute myelogenous leukemia containing the (8;21)(q22;q22) translocation.Blood. 1993;81:2860–2865.

    PubMed  CAS  Google Scholar 

  5. 5.

    Miyoshi H, Kozu T, Shimizu K, et al. The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript.EMBO J. 1993;7:2715–2721.

    Article  Google Scholar 

  6. 6.

    Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD. The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B.Oncogene. 1995;11:2667–2674.

    PubMed  CAS  Google Scholar 

  7. 7.

    Meyers S, Lenny N, Hiebert SW. The t(8; 21) fusion protein interferes with AML-1B-dependent transcriptional activation.Mol Cell Biol. 1995;15:1974–1982.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. 8.

    Burel SA, Harakawa N, Zhou L, Pabst T, Tenen DG, Zhang D-E. Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation.Mol Cell Biol. 2001;16:5577–5590.

    Article  Google Scholar 

  9. 9.

    Appelbaum FR, Kopecky KJ. Long-term survival after chemotherapy for acute myeloid leukemia: the experience of the Southwest Oncology Group.Cancer. 1997;80(suppl):2199–2204.

    Article  Google Scholar 

  10. 10.

    Miyamoto T, Nakafuji K, Akashi K, et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia.Blood. 1996;87:4789–4796.

    PubMed  CAS  Google Scholar 

  11. 11.

    Jurlander J, Caligiuri MA, Ruutu T, et al. Persistence of the AML1/ ETO fusion transcript in patients treated with bone marrow transplantation for t(8;21) leukemia.Blood. 1996;88:2183–2191.

    PubMed  CAS  Google Scholar 

  12. 12.

    Tobel K, Newton J, Macheta M, et al. Molecular quantification of minimal residual disease in acute myeloid leukemia with t(8;21) can identify patients in durable remission and predict clinical relapse.Blood. 2000;95:815–819.

    Google Scholar 

  13. 13.

    Satake N, Maseki N, Kozu T, et al. Disappearance of AML1-MTG8 (ETO) fusion transcript in acute myeloid leukaemia patients with t(8;21) in long-term remission.Br J Haematol. 1995;91:892–898.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Muto A, Mori S, Matsushita H, et al. Serial quantification of minimal residual disease of t(8;21) acute myelogenous leukemia with RT-competitive PCR assay.Br J Haematol. 1996;95:85–94.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Willis TG, Jadayel DM, Coignet LJA, et al. Rapid molecular cloning of rearrangements of the IGHJ locus using long-distance inverse polymerase chain reaction.Blood. 1997;90:2456–2464.

    PubMed  CAS  Google Scholar 

  16. 16.

    Akasaka H, Akasaka T, Kurata M, et al. Molecular anatomy of BCL6 translocations revealed by long-distance polymerase chain reaction-based assays.Cancer Res. 2000;60:2335–2341.

    PubMed  CAS  Google Scholar 

  17. 17.

    Peterson BA, Bloomfield CD. Prolonged maintained remissions of adult acute non-lymphocytic leukemia.Lancet. 1977;2:158–160.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Sauter C, Fehr J, Frick P, Gmuer J, Honegger H, Martz G. Acute myelogenous leukemia: successful treatment of relapse with cytosine arabinoside,VP 16-213, vincristine and vinblastine (A-triple V).Eur J Cancer Clin Oncol. 1982;18:733–737.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Sambrook J, Fritsch EF, Maniatis T.Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2001.

    Google Scholar 

  20. 20.

    Fey MF, Pilkington SP, Summers C, Wainscoat JS. Molecular diag nosis of haematological disorders using DNA from stored bone marrow slides.Br J Haematol. 1987;67:489–492.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M. t(8; 21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.Proc Natl Acad Sci U S A. 1991;88:10431–10434.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. 22.

    Shimizu K, Miyoshi H, Kozu T, et al. Consistent disruption of the AML1 gene occurs within a single intron in the t(8;21) chromosomal translocation.Cancer Res. 1992;52:6945–6948.

    PubMed  CAS  Google Scholar 

  23. 23.

    Erickson O, Gao J, Chang KS, et al. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity toDrosophila segmentation gene, runt.Blood. 1992;80:1825–1831.

    PubMed  CAS  Google Scholar 

  24. 24.

    Kozu T, Miyoshi H, Shimizu K, et al. Junctions of the AML1/MTG8 (ETO) fusion are constant in t(8;21) acute myeloid leukemia detected by reverse transcription polymerase chain reaction.Blood. 1993;82:1270–1276.

    PubMed  CAS  Google Scholar 

  25. 25.

    Tighe JE, Daga T, Calabi F. Translocation breakpoints are clustered on both chromosome 8 and chromosome 21 in the t(8;21) of acute myeloid leukemia.Blood. 1993;81:592–596.

    PubMed  CAS  Google Scholar 

  26. 26.

    Jowitt SN, Yin JA, Saunders MJ. Relapse myelodysplastic clone differs from acute onset clone as shown by X-linked DNA polymorphism patterns in a patient with acute myeloid leukemia.Blood. 1993;82:613–618.

    PubMed  CAS  Google Scholar 

  27. 27.

    Hayashi Y, Raimondi SC, Behm FG, et al. Two karyotypically independent leukemic clones with the t(8;21) and 11q23 translocation in acute myeloblastic leukemia at relapse.Blood. 1989;73:1650–1655.

    PubMed  CAS  Google Scholar 

  28. 28.

    Bernstein ML, Esseltine DW, Emond J, Vekemans M. Acute lymphoblastic leukemia at relapse in a child with acute myeloblastic leukemia.Am J Pediatr Hematol Oncol. 1986;8:153–157.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Rhoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model.Blood. 2000;96:2108–2115.

    PubMed  CAS  Google Scholar 

  30. 30.

    Lorsbach RB, Downing JR. The role of the AML1 transcription factor in leukemogenesis.Int J Hematol. 2001;74:258–265.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Marcucci G, Livak KI, Bi W, Strout MO, Bloomfield CD, Caligiuri MA. Detection of minimal residual disease in patients with AML1/ ETO-associated acute myeloid leukemia using a novel quantitative reverse transcription polymerase chain reaction assay.Leukemia. 1998;12:1482–1489.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Krauter J, Wattjes MP, Nagel S, et al. Real-time RT-PCR for the detection and quantification of AML1/MTG8 fusion transcripts in t(8;21)-positive AML patients.Br J Haematol. 1999;107:80–85.

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Morschhauser F, Cayuela JM, Martini S, et al. Evaluation of minimal residual disease using reverse-transcription polymerase chain reaction in t(8;21) acute myeloid leukemia: a multicenter study of 51 patients.J Clin Oncol. 2000;18:788–794.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Sugimoto T, Das H, Imoto S, et al. Quantification of minimal residual disease in t(8;21)-positive acute myelogenous leukemia patients using real-time quantitative RT-PCR.Am J Hematol. 2000;64:101–106.

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Grünewald K, Lyons J, Hansen-Hagge TE, Janssen JWG, Feichtinger H, Bartram CR. Molecular genetic analysis of DNA obtained from fixed, air dried or paraffin embedded sources.Ann Hematol. 1991;62:108–114.

    Article  PubMed  Google Scholar 

  36. 36.

    Shibata D, Martin WJ, Arnheim N. Analysis of DNA sequences in forty-year-old paraffin-embedded thin-tissue sections: a bridge between molecular biology and classical histology.Cancer Res. 1988;48:4564–4566.

    PubMed  CAS  Google Scholar 

  37. 37.

    Merkelbach S, Gehlen J, Handt S, Füzesi L. Novel enzyme immunoassay and optimized DNA extraction for the detection of polymerase-chain-reaction-amplified viral DNA from paraffinembedded tissue.Am J Pathol. 1997;150:1537–1546.

    PubMed  CAS  PubMed Central  Google Scholar 

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Correspondence to Norifumi Tsukamoto or Masamitsu Karasawa or Yoko Tanaka or Akihiko Yokohama or Hideki Uchiumi or Takafumi Matsushima or Hirokazu Murakami or Yoshihisa Nojima.

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Tsukamoto, N., Karasawa, M., Tanaka, Y. et al. Recurrence of Acute Myelogenous Leukemia with the SameAML1/ETO Breakpoint as at Diagnosis after Complete Remission Lasting 15 Years: Analysis of Stored Bone Marrow Smears. Int J Hematol 78, 362–369 (2003). https://doi.org/10.1007/BF02983563

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Key words

  • AML1/ETO gene
  • Long-term remission
  • Acute leukemia
  • Bone marrow slides