1. ¹Cell and Developmental Biology, Oregon Health & Science University, Portland, OR, USA
2. ²Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
3. ³Division of Hematology & Oncology, Oregon Health & Science University, Portland, OR, USA
4. ⁴Department of Pathology, Oregon Health & Science University, Portland, OR, USA
5. 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.