Invadopodia and rolling-type motility are specific features of highly invasive p190bcr-abl leukemic cells

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 (p210bcr-abl) or acute lymphoblastic leukemia, ALL (p190bcr-abl). The difference between p190bcr-abl and p210bcr-abl resides in the unique presence of the DH/PH domain in p210bcr-abl. Ba/F3 cells are not motile but acquire spontaneous motility upon ectopic expression of either p190bcr-abl or p210bcr-abl. Whereas p210bcr-abl-expressing cells present typical amoeboid motility, p190bcr-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 p210bcr-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/F3p190bcr-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 p190bcr-abl and correlates with an increase in Cdc42 activity. Such phenotype could also be obtained by impairing p210bcr-abl RhoA GEF function. Thus, invadopodia formation in association with rolling-type motility characterizes p190bcr-abl leukemic cells. The description of invadopodia in cells harboring the p190bcr-abl oncoprotein presents a novel feature of these highly invasive leukemic cells and provides a novel therapeutic drug target to treat the disease.