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.

  • Letter to the Editor
  • Published:

Low or undetectable numbers of Philadelphia chromosome-positive leukemic stem cells (Ph+CD34+CD38neg) in chronic myeloid leukemia patients in complete cytogenetic remission after tyrosine kinase inhibitor therapy

Leukemia volume 24, pages 219–222 (2010)Cite this article

To the Editor: Tyrosine kinase inhibitors (TKIs) efficiently induce rapid hematologic and cytogenetic responses in most chronic myeloid leukemia (CML) patients. TKI therapy has been considered to be life long, as rapid leukemia relapses are often observed in patients who discontinue treatment. The cause for relapse is unknown, but has been related to TKI resistance of the leukemic stem cells (LSCs) and/or immune tolerance of CML cells. Accordingly, in vitro experiments have suggested that TKIs have an antiproliferative, but not a proapoptotic or cytotoxic effect on the most primitive CML stem cells (Ph+ CD34+CD38neg cells).1, 2 Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment when compared to imatinib or nilotinib, but the drug was still unable to kill the most primitive CD34+CD38neg LSCs in vitro.2 The causes for stem cell resistance are unclear. In a recent study, primitive leukemic cells had higher BCR-ABL1 and CRKL kinase activity levels when compared with more mature cells. In addition, mRNA expression level of the imatinib uptake pump OCT-1 was lower and the drug efflux transporter protein ABCB1 (MDR) and ABCG2 levels were higher.3

The stem cell persistence has also been implied in previous publications showing small numbers of Ph+ CD34+ progenitor cells in bone marrow (BM) of CML patients even after years on TKI therapy.4, 5 However, recent observations suggest that in a substantial proportion of CML patients who have reached complete molecular remission during TKI treatment, therapy can be discontinued without imminent relapse of the disease.6 The molecular or cellular mechanisms for ‘cure’ are unknown, but either the therapy has eradicated the LSCs or they are under a transcriptional control by the immune system preventing stem cell proliferation and expansion. Thus far there are no reports describing the prevalence of the most primitive CML stem cells (CD34+CD38neg) in patients during TKI therapy. The aim of this project was to analyze the Philadelphia chromosome-positive (Ph+) LSCs in CML patients who have achieved a good response to TKI therapy.

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

Figure 1

References

  1. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319–325.

    Article  CAS  Google Scholar 

  2. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107: 4532–4539.

    Article  CAS  Google Scholar 

  3. Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 2007; 21: 926–935.

    Article  CAS  Google Scholar 

  4. Bocchia M, Ippoliti M, Gozzetti A, Abruzzese E, Calabrese S, Amabile M et al. CD34+/Ph+ cells are still detectable in chronic myeloid leukemia patients with sustained and prolonged complete cytogenetic remission during treatment with imatinib mesylate. Leukemia 2008; 22: 426–428.

    Article  CAS  Google Scholar 

  5. Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701–4707.

    CAS  Google Scholar 

  6. Mahon FX, Huguet F, Guilhot F, Legros L, Nicolini FE, Charbonnier A et al. Is it possible to stop imatinib in patients with chronic myeloid leukemia? An update from a French Pilot Study and first results from the multicentre « Stop Imatinib » (STIM) Study. Blood 2008; 112, Abstract 187.

  7. Takahashi N, Miura I, Saitoh K, Miura AB . Lineage involvement of stem cells bearing the Philadelphia chromosome in chronic myeloid leukemia in the chronic phase as shown by a combination of fluorescence-activated cell sorting and fluorescence in situ hybridization. Blood 1998; 92: 4758–4763.

    CAS  PubMed  Google Scholar 

  8. Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007; 25: 1315–1321.

    Article  CAS  Google Scholar 

  9. Copland M, Pellicano F, Richmond L, Allan EK, Hamilton A, Lee FY et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood 2008; 111: 2843–2853.

    Article  CAS  Google Scholar 

  10. Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA, Hassane DC et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 2007; 110: 4427–4435.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Finnish special governmental subsidy for health sciences, research, and training, by the Finnish Cancer Societies, Emil Aaltonen Foundation, Academy of Finland, Finnish Medical Foundation, Blood Disease Foundation, Biomedicum Helsinki Foundation, Gyllenberg Foundation, IGA NS 9949-3 and KA Johansson foundation. The authors would like to thank the personnel at the Hematology Research Unit at Helsinki and flow cytometry laboratory, HUSLAB for their expert technical assistance.

Author information

Authors and Affiliations

  1. Hematology Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland

    S Mustjoki, P Rohon, S Jalkanen, P Koskenvesa, T Lundán & K Porkka

  2. Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland

    S Mustjoki

  3. Department of Medicine, Division of Hematology, Helsinki University Central Hospital, Helsinki, Finland

    S Mustjoki, P Koskenvesa & K Porkka

  4. Department of Hemato-oncology, University Hospital Olomouc, Olomouc, Czech Republic

    P Rohon

  5. Department of Clinical Chemistry, Institute of Diagnostics, Oulu University Hospital, Oulu, Finland

    K Rapakko

  6. Laboratory of Molecular Pathology, HUSLAB, Helsinki University Central Hospital, Helsinki, Finland E-mail: kimmo.porkka@helsinki.fi,

    T Lundán

Authors
  1. S Mustjoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Rohon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Rapakko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Jalkanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Koskenvesa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Lundán
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Porkka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Porkka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mustjoki, S., Rohon, P., Rapakko, K. et al. Low or undetectable numbers of Philadelphia chromosome-positive leukemic stem cells (Ph+CD34+CD38neg) in chronic myeloid leukemia patients in complete cytogenetic remission after tyrosine kinase inhibitor therapy. Leukemia 24, 219–222 (2010). https://doi.org/10.1038/leu.2009.190

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.190

This article is cited by

Search

Advanced search

Quick links