Invadopodia and rolling-type motility are specific features of highly invasive p190(bcr-abl) leukemic cells

Eur J Cell Biol. Nov-Dec 2012;91(11-12):978-87. doi: 10.1016/j.ejcb.2012.04.006. Epub 2012 Jun 19.

Abstract

Philadelphia chromosome results of a reciprocal translocation between chromosome 9 and 22. The translocation generates a chimeric oncogene, which, depending on the precise location of the fusion causes chronic myelogenous leukemia, CML (p210(bcr-abl)) or acute lymphoblastic leukemia, ALL (p190(bcr-abl)). The difference between p190(bcr-abl) and p210(bcr-abl) resides in the unique presence of the DH/PH domain in p210(bcr-abl). Ba/F3 cells are not motile but acquire spontaneous motility upon ectopic expression of either p190(bcr-abl) or p210(bcr-abl). Whereas p210(bcr-abl)-expressing cells present typical amoeboid motility, p190(bcr-abl)-expressing cells motility appears dependent on rolling movements. Both motility types are triggered by Vav1 in complex with Bcr-Abl, and dependent on Rac1 activity. Interestingly, the RhoA specific p210(bcr-abl) DH/PH domain regulates the motility mode by shifting motility from a rolling type toward an amoeboid one. In this study, we show that Ba/F3p190(bcr-abl)-expressing cells assemble invadopodia-like structures visualized as dense F-actin dots containing the actin polymerization machinery and bestowed with matrix degradation activities. The formation of these structures is driven by the reduction of RhoA activity associated with the loss of the DH/PH domain in p190(bcr-abl) and correlates with an increase in Cdc42 activity. Such phenotype could also be obtained by impairing p210(bcr-abl) RhoA GEF function. Thus, invadopodia formation in association with rolling-type motility characterizes p190(bcr-abl) leukemic cells. The description of invadopodia in cells harboring the p190(bcr-abl) oncoprotein presents a novel feature of these highly invasive leukemic cells and provides a novel therapeutic drug target to treat the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Cell Line, Tumor
  • Cell Movement*
  • Cell Surface Extensions / metabolism*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Lymphocytes / ultrastructure
  • Neoplasm Invasiveness
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • cdc42 GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Actins
  • abl-bcr fusion protein, human
  • Fusion Proteins, bcr-abl
  • cdc42 GTP-Binding Protein
  • rhoA GTP-Binding Protein