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Nuclear entrapment of BCR–ABL by combining imatinib mesylate with leptomycin B does not eliminate CD34+ chronic myeloid leukaemia cells

Leukemia volume 23, pages 1006–1008 (2009)Cite this article

Chronic myeloid leukaemia (CML) arises from the formation of the Philadelphia (Ph+) chromosome in haematopoietic stem cells. The translated fusion oncoprotein, BCR–ABL (p210BCR−ABL), is a constitutively active tyrosine kinase (TK), which activates multiple proliferative and anti-apoptotic signalling pathways, causing deregulated cell growth.1 Despite impressive rates of complete cytogenetic response (CCyR) in the majority of patients treated with the targeted TK inhibitor (TKI), imatinib mesylate (IM; Glivec, Novartis, Basle, Switzerland),2 few patients achieve sustained molecular remission and a significant proportion develops resistance to IM.3 The presence of pre-existing or acquired BCR–ABL kinase domain mutations, which decrease IM binding,3 and the innate insensitivity of primitive quiescent CML stem cells to IM4 are two contributing resistance mechanisms. Consequently, many strategies have been investigated to overcome IM resistance, including the development of second-generation TKIs, nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol–Myers Squibb, Princeton, NJ, USA), although these remain ineffective against the T315I mutation.

In search of alternative strategies for the elimination of Ph+ cells, Vigneri and Wang 5showed an intriguing strategy of tricking BCR-ABL+ cells into committing cell death. This mechanism was based on the observation that on treatment with IM, inactive BCR-ABL translocates into the cell nucleus. Entrapment of BCR–ABL there, coupled with re-activation of its TK activity, reversed its role to that of an activator of apoptosis. On the basis of the mounting evidence that BCR–ABL+ stem cells are not eliminated by novel targeted therapies, such as IM and the second-generation TKIs, we investigated whether combination treatment of IM, with the nuclear export inhibitor leptomycin B (LMB Calbiochem), could drive CML CD34+ cells into apoptosis.

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Authors and Affiliations

  1. Division of Cancer Sciences and Molecular Pathology, Paul O'Gorman Leukaemia Research Centre, Section of Experimental Haematology, Faculty of Medicine, University of Glasgow, Glasgow, UK

    E K Allan, A Hamilton, S Hatziieremia, P Zhou, H G Jørgensen & T L Holyoake

  2. Academic Transfusion Medicine Unit, Scottish National Blood Transfusion Service, Glasgow, UK

    E K Allan

  3. Department of Biomedical Sciences, Section of General Pathology, University of Catania, Catania, Italy. E-mail: tlh1g@clinmed.gla.ac.uk,

    P Vigneri

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  1. E K Allan
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  2. A Hamilton
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  3. S Hatziieremia
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Allan, E., Hamilton, A., Hatziieremia, S. et al. Nuclear entrapment of BCR–ABL by combining imatinib mesylate with leptomycin B does not eliminate CD34+ chronic myeloid leukaemia cells. Leukemia 23, 1006–1008 (2009). https://doi.org/10.1038/leu.2008.367

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