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.

  • Correspondence
  • Published:

Do transcriptionally silent BCR-ABL cells persist in CML patients in molecular remission after stem cell transplantation?

Leukemia volume 15, pages 997–999 (2001)Cite this article

The only current curative treatment for chronic myeloid leukemia (CML) is allogeneic stem cell transplantation (SCT). However, relapses occur in 10–30% of patients transplanted in chronic phase and even more frequently in patients transplanted in later phases of CML. As relapses can appear after long-term molecular remissions detected by nested RT-PCR for BCR-ABL transcript, the question arises of what is the origin of cells whose activation results in a relapse. A rational explanation seems to be the persistence of cells with an unexpressed BCR-ABL gene. The question of existence of such transcriptionally silent BCR-ABL cells was addressed by several authors with contradictory conclusions. Zhang et al,1 when comparing the results of genomic DNA PCR for BCR-ABL with RT-PCR, found that CML patients in remission after SCT do not generally harbor a substantial pool of transcriptionally silent BCR-ABL cells. On the other hand, Chomel et al2 suppose the persistence of a significant number of dormant BCR-ABL cells in patients in complete cytogenetic remission after IFN treatment or SCT. They detected 1–12% nuclei with BCR-ABL fusion gene by fluorescent in situ hybridization (FISH) in peripheral blood or bone marrow from 21 patients (10 post-SCT), whereas RT-PCR tests were negative or only weakly positive (BCR-ABL/ABL close to 0.002%). In two patients with a sex-mismatched donor, the level of cells with the BCR-ABL genomic rearrangement was also confirmed by FISH using X and Y chromosome probes. The detected amount of quiescent cells is surprisingly high, particularly in patients after SCT (3–11%). This finding does not correspond with the results of the above authors1 and also with our own experience.

Our considerations result from the comparison of hematopoietic mixed chimerism analyses based on genomic DNA PCR for a variable number of tandem repeat (VNTR) sequences, and the level of BCR-ABL transcripts in peripheral blood samples from patients with CML after SCT. The chimerism analyses can identify the proportion of recipient and donor blood cells in post-SCT patients but do not distinguish between leukemic and normal recipient cells. However, the number of host cells clearly determines the highest possible number of leukemic cells while, on the other hand, the absence of host cell DNA unambiguously excludes the presence of leukemic cells with BCR-ABL genomic rearrangement of host cell origin at the sensitivity level of the method. The sensitivity of PCR for various VNTR loci, assessed by dilution of recipient cells into donor cells, was found to be 5–0.8% for ApoBII, Col2A1, YNZ22, HVR-Ig and TPO loci (higher sensitivity for short recipient alleles); 0.5% using D1S80 and MCT118 locus; 0.1–0.01% for AMG sex specific locus and 0.1–0.01% in 1st PCR and 0.001–0.0001% in 2nd PCR of two-step nested PCR for the sex-specific locus DYZ1 in female–male donor–recipient pairs.3 The presence and amount of the BCR-ABL transcripts were detected by qualitative and quantitative competitive two-step RT-PCR with a sensitivity of 0.001–0.0001% (10−5−10−6).4

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

References

  1. Zhang JG, Lin F, Chase A, Goldman JM, Cross NCP . Comparison of genomic DNA and cDNA for detection of residual disease after treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation Blood 1996 87: 2588–2593

    CAS  PubMed  Google Scholar 

  2. Chomel JC, Brizard F, Veinstein A, Rivet J, Sadoun A, Kitzis A, Guilhot F, Brizard A . Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-α therapy or allogeneic bone marrow transplantation Blood 2000 95: 404–408

    CAS  PubMed  Google Scholar 

  3. Formánková R, Honzátková L, Moravcová J, Sieglová Z, Dvoráková R, Nádvorníková S, Vítek A, Lukásová M, Starý J, Brdicčka R . Prediction and reversion of post-transplant relapse in patients with chronic myeloid leukemia using mixed chimerism and residual disease detection and adoptive immunotherapy Leukemia Res 2000 24: 339–347

    Article  Google Scholar 

  4. Moravcová J, Lukásová M, Starý J, Haskovec C . Simple competitive two-step RT-PCR assay to monitor minimal residual disease in CML patients after bone marrow transplantation Leukemia 1998 12: 1303–1312

    Article  Google Scholar 

  5. Holyoake T, Jiang X, Eaves C, Eaves A . Isolation of highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia Blood 1999 94: 2056–2064

    CAS  PubMed  Google Scholar 

  6. Serrano J, Roman J, Sanchez J, Jimenez A, Castillejo JA, Herrera C, Gonzales MG, Reina L, Rodrigues MC, Alvarez MA, Maldonado J, Torres A . Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210BCR-ABL and p190BCR-ABL after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190BCR-ABL detection precede cytogenetic relapse Blood 2000 95: 2659–2665

    CAS  PubMed  Google Scholar 

  7. Chase A, Parker S, Kaeda J, Sivalingam R, Cross NCP, Goldman JM . Absence of host-derived cells in the blood of patients in remission after allografting for chronic myeloid leukemia Blood 2000 96: 777–778

    CAS  PubMed  Google Scholar 

  8. Deininger M, Lehmann T, Krahl R, Hennig E, Müller Ch, Niederwieser D . No evidence for persistence of BCR-ABL positive cells in patients in molecular remission after conventional allogeneic transplantation for chronic myeloid leukemia Blood 2000 96: 778–779

    CAS  Google Scholar 

Download references

Acknowledgements

We thank clinicians from the Institute of Hematology and Blood Transfusion and 2nd Medical School of Charles University in Prague for providing us with patient samples and Dr. Michalová’s cytogenetic group for cytogenetic information. The studies were supported by grants 4918–3, 5902–3 and CEZMZ 0023736001 from the Internal Grant Agency of Ministry of Health of the Czech Republic.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Institute of Hematology and Blood Transfusion, Prague, Czech Republic

    J Moravcová, S Nádvorníkova, Z Sieglová, L Krsková, R Dvořáková & R Brdička

  2. 2nd Department of Pediatrics, 2nd Medical School, Charles University, Prague, Czech Republic

    R Formánková

Authors
  1. J Moravcová
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Nádvorníkova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Z Sieglová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Formánková
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L Krsková
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Dvořáková
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Brdička
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moravcová, J., Nádvorníkova, S., Sieglová, Z. et al. Do transcriptionally silent BCR-ABL cells persist in CML patients in molecular remission after stem cell transplantation?. Leukemia 15, 997–999 (2001). https://doi.org/10.1038/sj.leu.2402136

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402136

This article is cited by

Search

Advanced search

Quick links