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.
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.
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA. ghosh.asish@mayo.edu
Asish K
AK
Ghosh
Charla
C
Secreto
Justin
J
Boysen
Traci
T
Sassoon
Tait D
TD
Shanafelt
Debabrata
D
Mukhopadhyay
Neil E
NE
Kay
D000814:Aniline Compounds / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001567:Benzocycloheptenes / Q000494:pharmacology; D001665:Binding Sites; D018920:Coculture Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017154:Stromal Cells / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase
D000814:Aniline Compounds; D001567:Benzocycloheptenes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D014230:Triazoles; C548378:bemcentinib; C471992:bosutinib; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human