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Chronic Myeloid Leukemia, BCR/ABL Studies and Myelo Proliferative Disorders

Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia

Leukemia volume 19, pages 1590–1596 (2005)Cite this article

Abstract

Selective inhibition of the BCR/ABL tyrosine kinase by imatinib has become a first-line therapy for chronic myelogenous leukemia (CML). However, BCR/ABL-positive progenitors often persist despite treatment, and relapse associated with resistance to imatinib has been described in many patients with advanced disease. Drug efflux by P-glycoprotein (P-gp), as well as point mutations in BCR/ABL oncoprotein, has been implicated in the mechanism of resistance to imatinib. In this study, we established a murine transplantation model of CML-like myeloproliferative disease using Mdr1a/1b-null mice and analyzed the effects of loss of P-gp on resistance to imatinib. We found that mice transplanted with Mdr1a/1b-null bone marrow (BM) that had been transduced with a BCR/ABL retroviral vector displayed similar responses to imatinib, compared with those transplanted with BCR/ABL-transduced wild-type BM. In the absence of P-gp, the incidence and latency of disease in secondary recipients was not changed in imatinib-treated mice, relative to wild-type controls. Furthermore, K562 cells engineered to overexpress P-gp remained sensitive to imatinib-induced growth inhibition and cell death. Together, our findings suggest that P-gp expression in hematopoietic stem cells does not significantly contribute to imatinib resistance in CML.

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Acknowledgements

We thank Flow Cytometry Lab and Animal Diagnostic Lab for sample analysis. This study is supported by NIH Grant R01 HL67366 (to BPS), by the American Lebanese Syrian Associated Charities and by the Hal and Alma Reagan Fellowship.

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Authors and Affiliations

  1. Division of Experimental Hematology, Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA

    Y Zong, S Zhou & B P Sorrentino

  2. The Interdisciplinary Program, College of Graduate Health Sciences, the University of Tennessee Health Science Center, Memphis, TN, USA

    Y Zong & B P Sorrentino

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Correspondence to B P Sorrentino.

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Zong, Y., Zhou, S. & Sorrentino, B. Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia. Leukemia 19, 1590–1596 (2005). https://doi.org/10.1038/sj.leu.2403853

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