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A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib

Leukemia volume 20, pages 2057–2060 (2006)Cite this article

Resistance to imatinib in the treatment of chronic myelogenous leukemia (CML) may occur due to amplification of the Bcr-Abl gene, but more frequently by point mutations causing substitutions of critical amino-acid residues in the Abl kinase domain.1 More than 40 different mutations have been described so far.2 They confer resistance due to amino-acid substitutions, which impair drug binding without influencing ATP binding.3 Here, we describe the clinical and molecular features of two imatinib-resistant CML patients (‘A’ and ‘B’) bearing the L248V mutation in the Bcr-Abl kinase domain. Interestingly, this mutation, a C to G transversion at position 1106, activates a cryptic splice donor sequence. Awareness of this deleted isoform seems essential to secure correct diagnosis of the L248V mutation, particularly when using sequencing, as mixed sequences will occur.

Both patients expressed mutant Bcr-Abl alleles with the normal and variant (Δ248–274)-splice isoforms. To further investigate the frequency of the (Δ248–274)-splice isoform, we sequenced 10 individual cDNA clones from each subject. In A, three clones represented this isoform and in B only one out of 10. For both subjects, all the clones representing the normal isoform contained the mutated G at position 1106 (data not shown).

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Acknowledgements

We thank Per Arne Standal for providing patient samples and Mikhail Sovershaev for support in graphical design. This study was supported by a grant given by the Northern Norwegian Health Authorities (SFP 54-06).

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Pharmacy, University of Tromsø, Tromsø, Norway

    F X Gruber & I Mikkola

  2. Department of Hematology, St Olavs Hospital, Trondheim, Norway

    H Hjorth-Hansen

  3. Hematology Centre, Karolinska University Hospital and Institute, Stockholm, Sweden

    L Stenke

  4. Department of Biochemistry, Institute of Medical Biology, University of Tromsø, Tromsø, Norway

    T Johansen

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  1. F X Gruber
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Gruber, F., Hjorth-Hansen, H., Mikkola, I. et al. A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib. Leukemia 20, 2057–2060 (2006). https://doi.org/10.1038/sj.leu.2404400

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