BCR-ABL-induced adhesion defects are tyrosine kinase-independent

Jason A. Wertheim, Kevin Forsythe, Brian J. Druker, Daniel Hammer, David Boettiger, Warren S. Pear

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

The t(9;22) chromosomal translocation results in expression of P210BCR-ABL a fusion protein necessary for the development of chronic myelogenous leukemia (CML). The constitutive activation of the P210BCR-ABL tyrosine kinase results in phosphorylation of multiple signaling pathways leading to the transformed phenotype. Additionally, extracellular interactions between P210BCR-ABL-expressing progenitor cells and bone marrow stroma may provide external signals that facilitate CML development. In contrast to the intracellular signaling pathways involved in CML, little is known about how P210BCR-ABL expression modifies cell-cell and cell-substratum interactions. To investigate the role of P210BCR-ABL in modulating cellular adhesion, we used a highly sensitive and quantitative cell detachment apparatus that measures the strength of association between a population of cells and an adhesive matrix. Our findings show that P210BCR-ABL expression increased adhesion nearly 2-fold between the myeloblastic cell line, 32D, and fibronectin compared to a control vector. We then investigated whether abnormal adhesion due to P210BCR-ABL expression was caused by its tyrosine kinase activity. A quantitative analysis of cell-fibronectin adhesion found that neither expression of a kinase-inactive P210BCR-ABL mutant in 32D cells or attenuation of kinase activity by STI571 (imatinib mesylate) in 32D cells transduced with wild-type P210BCR-ABL could correct the nearly 2-fold increase in cell-fibronectin adhesion. Similarly, STI571 treatment of Meg-01 cells, a P210BCR-ABL- expressing cell line derived from a patient in blast crisis, failed to inhibit adhesion to fibronectin. Together, our results indicate that changes in adhesion induced by P210BCR-ABL are independent of its tyrosine kinase activity.

Original languageEnglish (US)
Pages (from-to)4122-4130
Number of pages9
JournalBlood
Volume99
Issue number11
DOIs
StatePublished - Jun 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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