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:

Analysis of BCR–ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells suggests a unique mutator phenotype

Leukemia volume 24, pages 1817–1821 (2010)Cite this article

Subjects

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by a BCR–ABL1 fusion gene, usually resulting from a reciprocal t(9;22) translocation.1 The identification of this abnormality led to the development of therapies that selectively inhibit the activity of the BCR–ABL1 tyrosine kinase (TK) oncoprotein.2 Imatinib mesylate (IM), the first such inhibitor, has shown considerable effectiveness in chronic phase CML (CP-CML).2 Nevertheless, acquired and intrinsic drug resistance remains a significant clinical problem in CML patients, with amino acid mutations in the BCR–ABL1 TK domain accounting for 60–90% of relapses.3 Although some mutations result in amino acid changes conferring IM-resistant phenotypes, others have no significant impact on drug efficacy, but may serve as independent prognostic markers of a poor clinical outcome.3 Primitive (CD34+) CP-CML cells are intrinsically insensitive to IM and genetically unstable.4 They persist in IM-treated patients and constitute a reservoir from which IM-resistant mutant clones can be generated. BCR–ABL1 TK domain mutations are detected in CD34+ CP-CML cells before IM treatment, however, the mechanism by which they arise is unknown.4

We observed a similar pattern of BCR–ABL1 TK codon position mutations in sequences derived from IM-resistant cells at position 1 and overall. These included a significant A-to-G bias (A>G, P=0.011 and 0.006, respectively) and a significant under-representation of C-to-T transitions (C>T, 1.31 × 10−9 and 0.030, respectively, Figure 1b). It is interesting that in IM-resistant cells, A-to-T (A>T) transversions were over-represented at position 2 and overall (1.41 × 10−11 and 3.77 × 10−5, respectively, Figures 1b and 2b). These cells also had a profound transversional bias (1.45 × 10−4) at codon position 3, suggesting that positive selection occurs at a position where transversions are typically non-synonymous.6

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

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
Figure 2
Figure 3

References

  1. Goldman JM, Melo JV . Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med 2003; 349: 1451–1464.

    Article  CAS  Google Scholar 

  2. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  Google Scholar 

  3. Apperley JF . Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1018–1029.

    Article  CAS  Google Scholar 

  4. Jiang X, Saw KM, Eaves A, Eaves C . Instability of BCR-ABL gene in primary and cultured chronic myeloid leukemia stem cells. J Natl Cancer Inst 2007; 99: 680–693.

    Article  CAS  Google Scholar 

  5. Jiang C, Zhao Z . Mutational spectrum in the recent human genome inferred by single nucleotide polymorphisms. Genomics 2006; 88: 527–534.

    Article  CAS  Google Scholar 

  6. Bofkin L, Goldman N . Variation in evolutionary processes at different codon positions. Mol Biol Evol 2007; 24: 513–521.

    Article  CAS  Google Scholar 

  7. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL . Over riding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305: 399–401.

    Article  CAS  Google Scholar 

  8. Klemm L, Duy C, Iacobucci I, Kuchen S, von Levetzow G, Feldhahn N et al. The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia. Cancer Cell 2009; 16: 232–245.

    Article  CAS  Google Scholar 

  9. Kulinskaya E . On two-sided P-values for nonsymmetric distributions. Arxiv 2008; 0810: 2124.

    Google Scholar 

Download references

Acknowledgements

The authors thank members of the Leukemia/Bone Marrow Transplant Program of British Columbia for facilitating access to CML patients’ samples and clinical data; the Terry Fox Laboratory FACS Facility for assistance in cell sorting; the Stem Cell Assay Laboratory for cell processing and cryopreservation of CML samples; K Saw and K Lambie for excellent technical assistance; and Prof Richard I Christopherson (University of Sydney) and Prof Michael Neuberger (MRC Laboratory of Molecular Biology, Cambridge) for useful discussion. This work was supported in part by grants from the Canadian Cancer Society Research Institute (to XJ, AE and CE), the Cancer Research Society, the Leukemia & Lymphoma Society of Canada and the Canadian Cancer Society (to XJ) with core infrastructure support from the British Columbia Cancer Foundation. X Jiang is Michael Smith Foundation for Health Research Scholar.

Author information

Author notes

  1. H Grant and X Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Mathematics, University College London, London, UK

    H Grant & K Page

  2. British Columbia Cancer Agency and Department of Medical Genetics, Terry Fox Laboratory, University of British Columbia, Vancouver, BC, Canada

    X Jiang & C J Eaves

  3. Department of Medical Oncology, Centre for Haematology, Imperial College, London, UK

    J Stebbing

  4. Department of Medicine, Centre for Haematology, Imperial College, London, UK

    L Foroni, J S Khorashad & G Gerrard

  5. Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK

    C Craddock

  6. West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK

    M Griffiths

  7. Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK

    R E Clark & L Wang

  8. Northern Institute for Cancer Research, Newcastle University Medical School, Newcastle upon Tyne, UK

    S O'Brien & J A E Irving

  9. Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, UK

    M Wang

  10. MRC Toxicology Unit, University of Leicester, Hodgkin Building, Leicester, UK

    L Karran & M J S Dyer

  11. Division of Hematology, Leukaemia/BMT Program of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada

    D Forrest

  12. Discovery Medicine Oncology, Bristol-Myers Squibb, Princeton, NJ, USA

    A Woolfson

Authors
  1. H Grant
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Stebbing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Foroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C Craddock
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R E Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S O'Brien
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J S Khorashad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Gerrard
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J A E Irving
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L Karran
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M J S Dyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. D Forrest
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. K Page
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. C J Eaves
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. A Woolfson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C J Eaves.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grant, H., Jiang, X., Stebbing, J. et al. Analysis of BCR–ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells suggests a unique mutator phenotype. Leukemia 24, 1817–1821 (2010). https://doi.org/10.1038/leu.2010.179

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.179

This article is cited by

Search

Advanced search

Quick links