Aberrant expression of c-met and HGF/c-met pathway provides survival advantage in B-chronic lymphocytic leukemia.
BACKGROUND
B-chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of CD5(+) B lymphocytes. Decreased VLA-4 (Cd49d/CD29) and CD11a expression and defective adhesion in B-CLL have been previously shown, although there was no substantial data about its importance in immunobiology of B-CLL. The hepatocyte growth factor (HGF) receptor, c-met, plays a role in adhesion by acting on VLA-4. c-met and VLA-4 share crucial signaling molecules in cell survival. In this study, relationship between expressions of c-met and CD49d, CD11a, and additional common signaling molecules in B-CLL was investigated.


METHODS
White blood cells from 24 patients with CLL were studied by flow cytometry and/or western blotting prior to and after culturing with recombinant HGF. HGF level from sera was measured with a bead-based flow cytometric assay.


RESULTS
c-metα and c-metβ were expressed on B-CLL cells, while no expression was observed on normal donor CD19+ cells. This increase was inversely correlated with decreased expression of adhesion molecules. Serum level of HGF in B-CLL was found to be increased. In vitro experiments showed that HGF supported survival in B-CLL cells supporting the possible function of HGF/c-met pathway in B-CLL. Furthermore, expressions of critical signaling molecules shared by both VLA-4 and HGF/c-met systems including Bcl-XL, Akt, PI3K, and phospho-bad(136) following HGF stimulations of B-CLL cells have been found to be increased.


CONCLUSIONS
Increased expression of c-met and HGF may bypass the importance of expression of critical adhesion molecules and support survival of B-CLL cells. c-met, being one of the surface tyrosine kinases, may serve as a target for future therapies in B-CLL meriting more attention.
Eksioglu-Demiralp
Emel
E
Department of Hematology-Immunology, School of Medicine, Marmara University, Istanbul, Turkey. demiralp@marmara.edu.tr
Akdeniz
Tuba
T
Bayik
Mahmut
M
D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D016022:Case-Control Studies; D002448:Cell Adhesion; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D017228:Hepatocyte Growth Factor / Q000097:blood* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D039441:Integrin alpha4 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494819:BAD protein, human; C494811:BCL2L1 protein, human; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D039441:Integrin alpha4; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met