The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy.

Publication Type:

Journal Article

Source:

Blood, Volume 117, Issue 6, p.1928-37 (2011)

Keywords:

Aniline Compoundsdigestive disease, digestive deseases Apoptosisdigestive disease, digestive deseases B-Lymphocytesdigestive disease, digestive deseases Benzocycloheptenesdigestive disease, digestive deseases Binding Sitesdigestive disease, digestive deseases Coculture Techniquesdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Leukemia, Lymphocytic, Chronic, B-Celldigestive disease, digestive deseases Nitrilesdigestive disease, digestive deseases Phosphorylationdigestive disease, digestive deseases Protein Kinase Inhibitorsdigestive disease, digestive deseases Protein Kinasesdigestive disease, digestive deseases Proto-Oncogene Proteinsdigestive disease, digestive deseases Proto-Oncogene Proteins c-bcl-2digestive disease, digestive deseases Quinolinesdigestive disease, digestive deseases Receptor Protein-Tyrosine Kinasesdigestive disease, digestive deseases src-Family Kinasesdigestive disease, digestive deseases Stromal Cellsdigestive disease, digestive deseases Triazoles

Abstract:

Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell-derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/ζ-associated protein of 70 kDa, phospholipase C γ2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI-606), or a specific-inhibitor of Axl (R428), robust induction of CLL B-cell apoptosis was observed in both a dose- and time-dependent manner. Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment.