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Prepublished online as a Blood First Edition Paper on June 5, 2003; DOI 10.1182/blood-2003-01-0062.
Submitted January 8, 2003
Accepted May 10, 2003
Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development
Jason A Wertheim, Samanthi A Perera, Daniel A Hammer, Ruibao Ren, David Boettiger, and Warren S Pear*
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA
Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA
Department of Biology, Brandeis University, Waltham, MA, USA
* Corresponding author; email: wpear{at}mail.med.upenn.edu.
We have previously found that P210BCR-ABL increases the adhesion of hematopoietic cell lines to fibronectin by a mechanism that is independent of tyrosine kinase activity. To investigate the pathway(s) by which P210BCR-ABL influences cell adhesion, we used a quantitative cell adhesion device that can discern small changes in cell adhesion to assay P210BCR-ABL with mutations in several critical domains. We expressed P210BCR-ABL mutants in 32D myeloblast cells and found that binding to fibronectin is primarily mediated by the  5 1 integrin. We performed a structure/function analysis to map domains important for cell adhesion. Increased adhesion was mediated by three domains: i) the N-terminal coiled-coiled domain that facilitates oligomerization and F-actin localization, ii) bcr sequences between aa 163 to 210, and iii) F-actin localization through the C-terminal actin binding domain of c-abl. We compared our adhesion results with the ability of these mutants to cause a CML-like disease in a murine bone marrow transplant assay and found that adhesion to fibronectin did not correlate with the ability of these mutants to cause CML. Together, our results suggest that F-actin localization may play a pivotal role in modulating adhesion, but that it is dispensable for development of CML.
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