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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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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DOI: https://doi.org/10.1038/leu.2008.65
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