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Chronic Myeloproliferative Disorders

Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia

Leukemia volume 22, pages 1184–1190 (2008)Cite this article

Abstract

The BCR-ABL oncogenic tyrosine kinase causes chronic myeloid leukemia and is the target for imatinib therapy. During imatinib treatment, cells are selected in some patients with BCR-ABL kinase domain mutations that render decreased drug sensitivity. In addition, some patients express deletion mutants of BCR-ABL, apparently due to missplicing. Most commonly these deletion mutants lack a significant portion of the kinase domain that includes the P-loop. We describe a screen for such mutations in patients with CML and demonstrate that they are not oncogenic and are catalytically inactive. We hypothesized that coexpressing BCR-ABL deletion mutants has a dominant-negative effect on the native form through heterocomplex formation. However, upon coexpression of native and deletion mutant BCR-ABL in Ba/F3 cells, growth factor independence is maintained and signaling is activated normally. Despite this, these cells have increased imatinib sensitivity compared to cells expressing only native BCR-ABL. Thus, it will be important to investigate the prognostic impact of coexpression of deletion mutants in CML patients during imatinib treatment.

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Acknowledgements

Supported in part by NHLBI Grant HL082978-01 (MWD), Doris Duke Charitable Foundation (BJD) and the Leukemia and Lymphoma Society (BJD, MWD).

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Authors and Affiliations

  1. Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA

    D W Sherbenou & B J Druker

  2. Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    O Hantschel, I Kaupe & G Superti-Furga

  3. Division of Hematology & Oncology, Oregon Health & Science University, Portland, OR, USA

    L Turaga, S Willis, T Bumm, B J Druker & M W Deininger

  4. Department of Pathology, Oregon Health & Science University, Portland, OR, USA

    R D Press

  5. Howard Hughes Medical Institute, Portland, OR, USA

    B J Druker

Authors
  1. D W Sherbenou
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  2. O Hantschel
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  3. L Turaga
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  4. I Kaupe
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  5. S Willis
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  6. T Bumm
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  7. R D Press
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  8. G Superti-Furga
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  9. B J Druker
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  10. M W Deininger
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Corresponding author

Correspondence to M W Deininger.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Sherbenou, D., Hantschel, O., Turaga, L. et al. Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia. Leukemia 22, 1184–1190 (2008). https://doi.org/10.1038/leu.2008.65

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