Original Article
Leukemia (2008) 22, 1184–1190; doi:10.1038/leu.2008.65; published online 20 March 2008
Chronic Myeloproliferative Disorders
Characterization of BCR-ABL deletion mutants from patients with chronic myeloid leukemia
D W Sherbenou1, O Hantschel2, L Turaga3, I Kaupe2, S Willis3, T Bumm3, R D Press4, G Superti-Furga2, B J Druker1,3,5 and M W Deininger3
- 1Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA
- 2Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- 3Division of Hematology & Oncology, Oregon Health & Science University, Portland, OR, USA
- 4Department of Pathology, Oregon Health & Science University, Portland, OR, USA
- 5Howard Hughes Medical Institute, Portland, OR, USA
Correspondence: Dr MW Deininger, Hematology and Medical Oncology, Oregon Health & Science University, L592, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. E-mail: deininge@ohsu.edu
Received 8 December 2007; Revised 19 February 2008; Accepted 21 February 2008; Published online 20 March 2008.
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.
Keywords:
CML, kinase domain, imatinib, deletion mutations
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Nature Reviews Cancer Review (01 May 2007)
Dual tyrosine kinase inhibitors in chronic myeloid leukemia
Leukemia Review
NEWS AND VIEWS
Inhibitors of Bcr-abl. breaking new ground again
Nature Chemical Biology News and Views (01 Feb 2006)
Nature Chemical Biology News and Views (01 Apr 2009)
