Blood, 2011-02, Vol.117 (6), p.1928-1937
2011
Details
- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Blood, 2011-02, Vol.117 (6), p.1928-1937
- Ort / Verlag
- Washington, DC: Elsevier Inc
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0006-4971, 1528-0020eISSN: 1528-0020DOI: 10.1182/blood-2010-09-305649Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3056640
- Format
- –
- Schlagworte
- Aniline Compounds - pharmacology, Apoptosis, Apoptosis - drug effects, Apoptosis - physiology, Axl Receptor Tyrosine Kinase, B-Lymphocytes - drug effects, B-Lymphocytes - enzymology, B-Lymphocytes - pathology, Benzocycloheptenes - pharmacology, Binding Sites, Biological and medical sciences, Coculture Techniques, Hematologic and hematopoietic diseases, Humans, Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell - enzymology, Leukemia, Lymphocytic, Chronic, B-Cell - pathology, Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis, Lymphoid Neoplasia, Medical sciences, Myeloid Cell Leukemia Sequence 1 Protein, Nitriles - pharmacology, Phosphorylation, Protein Kinase Inhibitors - pharmacology, Protein Kinases - metabolism, Proto-Oncogene Proteins - antagonists & inhibitors, Proto-Oncogene Proteins - metabolism, Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors, Quinolines - pharmacology, Receptor Protein-Tyrosine Kinases - antagonists & inhibitors, Receptor Protein-Tyrosine Kinases - metabolism, src-Family Kinases - antagonists & inhibitors, src-Family Kinases - metabolism, Stromal Cells - drug effects, Triazoles - pharmacology