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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.

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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.

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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

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Correspondence to K Porkka.

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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

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