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.

  • Original Article
  • Published:

Chronic Myeloid Leukemia

Poor correlation of kinetics between BCR-ABL and WT1 transcript levels after allogeneic stem cell transplantation

Summary:

After allogeneic stem cell transplantation (SCT), we evaluated the use of the Wilms’ tumor gene (WT1) as a minimal residual disease (MRD) marker in 32 patients (28 chronic myeloid leukemia, three acute lymphoblastic leukemia and one acute myeloid leukemia). All patients expressed BCR-ABL and the kinetics of WT1 were compared with those of BCR-ABL using real-time quantitative PCR. WT1 expression was seen in the peripheral blood (PB) of healthy controls with a median expression level of 7 × 10−5 (WT1/ABL ratio). The corresponding values for BCR-ABL-negative and BCR-ABL-positive patient samples were 1 × 10−4 and 1.6 × 10−4, respectively. Kinetic studies in individual patients showed that WT1 and BCR-ABL levels usually did not copy each other. In four out of six patients who relapsed, an increase in WT1 from the background level (10−4) was observed only at the time of or after relapse, and in two patients increasing WT1 levels were observed before the relapse. In addition, the WT1 values found at the time of relapse were only two logs higher than the background level, indicating a sensitivity of 10−2. In conclusion, there is a constitutive low expression of WT1 in normal hematopoietic cells. The sensitivity and ability of WT1 to predict a relapse were poor in this study.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Maurer J, Janssen JW, Thiel E et al. Detection of chimeric BCR-ABL genes in acute lymphoblastic leukaemia by the polymerase chain reaction. Lancet 1991; 337: 1055–1058.

    Article  CAS  PubMed  Google Scholar 

  2. Paietta E, Racevskis J, Bennett JM et al. Biologic heterogeneity in Philadelphia chromosome-positive acute leukemia with myeloid morphology: the Eastern Cooperative Oncology Group experience. Leukemia 1998; 12: 1881–1885.

    Article  CAS  PubMed  Google Scholar 

  3. Cross NC, Feng L, Chase A et al. Competitive polymerase chain reaction to estimate the number of BCR-ABL transcripts in chronic myeloid leukemia patients after bone marrow transplantation. Blood 1993; 82: 1929–1936.

    CAS  PubMed  Google Scholar 

  4. Olavarria E, Kanfer E, Szydlo R et al. Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2001; 97: 1560–1565.

    Article  CAS  PubMed  Google Scholar 

  5. Radich JP, Gehly G, Gooley T et al. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 1995; 85: 2632–2638.

    CAS  PubMed  Google Scholar 

  6. Radich J, Gehly G, Lee A et al. Detection of bcr-abl transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia after marrow transplantation. Blood 1997; 89: 2602–2609.

    CAS  PubMed  Google Scholar 

  7. Inoue K, Sugiyama H, Ogawa H et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–3079.

    CAS  PubMed  Google Scholar 

  8. Bergmann L, Miething C, Maurer U et al. High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 1997; 90: 1217–1225.

    CAS  PubMed  Google Scholar 

  9. Kreuzer KA, Saborowski A, Lupberger J et al. Fluorescent 5′-exonuclease assay for the absolute quantification of Wilms’ tumour gene (WT1) mRNA: implications for monitoring human leukaemias. Br J Haematol 2001; 114: 313–318.

    Article  CAS  PubMed  Google Scholar 

  10. Miwa H, Beran M, Saunders GF . Expression of the Wilms’ tumor gene (WT1) in human leukemias. Leukemia 1992; 6: 405–409.

    CAS  PubMed  Google Scholar 

  11. Miyagi T, Ahuja H, Kubota T et al. Expression of the candidate Wilm's tumor gene, WT1, in human leukemia cells. Leukemia 1993; 7: 970–977.

    CAS  PubMed  Google Scholar 

  12. Inoue K, Ogawa H, Yamagami T et al. Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood 1996; 88: 2267–2278.

    CAS  PubMed  Google Scholar 

  13. Kletzel M, Olzewski M, Huang W, Chou PM . Utility of WT1 as a reliable tool for the detection of minimal residual disease in children with leukemia. Pediatr Dev Pathol 2002; 5: 269–275.

    Article  PubMed  Google Scholar 

  14. Ogawa H, Tamaki H, Ikegame K et al. The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 2003; 101: 1698–1704.

    Article  CAS  PubMed  Google Scholar 

  15. Gaiger A, Schmid D, Heinze G et al. Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia 1998; 12: 1886–1894.

    Article  CAS  PubMed  Google Scholar 

  16. Elmaagacli AH, Beelen DW, Trenschel R, Schaefer UW . The detection of wt-1 transcripts is not associated with an increased leukemic relapse rate in patients with acute leukemia after allogeneic bone marrow or peripheral blood stem cell transplantation. Bone Marrow Transplant 2000; 25: 91–96.

    Article  CAS  PubMed  Google Scholar 

  17. Schmid D, Heinze G, Linnerth B et al. Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia. Leukemia 1997; 11: 639–643.

    Article  CAS  PubMed  Google Scholar 

  18. Mattsson J, Uzunel M, Brune M et al. Mixed chimaerism is common at the time of acute graft-versus-host disease and disease response in patients receiving non-myeloablative conditioning and allogeneic stem cell transplantation. Br J Haematol 2001; 115: 935–944.

    Article  CAS  PubMed  Google Scholar 

  19. Ringden O, Remberger M, Persson U et al. Similar incidence of graft-versus-host disease using HLA-A, -B and -DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995; 15: 619–625.

    CAS  PubMed  Google Scholar 

  20. Carlens S, Ringden O, Aschan J et al. Risk factors in bone marrow transplant recipients with leukaemia. Increased relapse risk in patients treated with ciprofloxacin for gut decontamination. Clin Transplant 1998; 12: 84–92.

    CAS  PubMed  Google Scholar 

  21. Giralt SA, Champlin RE . Leukemia relapse after allogeneic bone marrow transplantation: a review. Blood 1994; 84: 3603–3612.

    CAS  PubMed  Google Scholar 

  22. Thomas ED, Buckner CD, Banaji M et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977; 49: 511–533.

    CAS  PubMed  Google Scholar 

  23. Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 1995; 86: 2041–2050.

    CAS  PubMed  Google Scholar 

  24. Bader P, Klingebiel T, Schaudt A et al. Prevention of relapse in pediatric patients with acute leukemias and MDS after allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed chimerism: a single center experience of 12 children. Leukemia 1999; 13: 2079–2086.

    Article  CAS  PubMed  Google Scholar 

  25. Dazzi F, Szydlo RM, Cross NC et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000; 96: 2712–2716.

    CAS  PubMed  Google Scholar 

  26. Cilloni D, Gottardi E, De Micheli D et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 2002; 16: 2115–2121.

    Article  CAS  PubMed  Google Scholar 

  27. Cross NC . Minimal residual disease in chronic myeloid leukaemia. Hematol Cell Ther 1998; 40: 224–228.

    CAS  PubMed  Google Scholar 

  28. Emig M, Saussele S, Wittor H et al. Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR. Leukemia 1999; 13: 1825–1832.

    Article  CAS  PubMed  Google Scholar 

  29. Lin F, Goldman JM, Cross NC . A comparison of the sensitivity of blood and bone marrow for the detection of minimal residual disease in chronic myeloid leukaemia. Br J Haematol 1994; 86: 683–685.

    Article  CAS  PubMed  Google Scholar 

  30. Coustan-Smith E, Sancho J, Hancock ML et al. Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 2002; 100: 2399–2402.

    Article  CAS  PubMed  Google Scholar 

  31. van der Velden VH, Jacobs DC, Wijkhuijs AJ et al. Minimal residual disease levels in bone marrow and peripheral blood are comparable in children with T cell acute lymphoblastic leukemia (ALL), but not in precursor-B-ALL. Leukemia 2002; 16: 1432–1436.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the staff at the Center for Allogeneic Stem Cell Transplantation and the Departments of Pediatrics and Hematology for excellent and skilful patient care. We also thank Dr Albert Bekassy for the help with some of the patient data. This study was supported by grants from the Swedish Cancer Society (0070-B99-13XAC), the Children's Cancer Foundation (2000/067), the Swedish Medical Research Council (K2000-06X-05971-20A), the Cancer Society in Stockholm and the Tobias Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Uzunel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Uzunel, M., Ringdén, O. Poor correlation of kinetics between BCR-ABL and WT1 transcript levels after allogeneic stem cell transplantation. Bone Marrow Transplant 33, 47–52 (2004). https://doi.org/10.1038/sj.bmt.1704296

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704296

Keywords

This article is cited by

Search

Quick links