c-Abl expression in chronic lymphocytic leukemia cells: clinical and therapeutic implications.
c-Abl is important for normal B-cell development, but little is known about the function of this nonreceptor tyrosine kinase in chronic lymphocytic leukemia (CLL). Therefore, the aim of the present study was to examine the clinical, therapeutic, and pathogenetic importance of c-Abl in this disease. We show that the malignant cells of CLL predominantly express the type 1b splice variant of c-Abl and that the expression of c-Abl protein is higher in CLL cells than in normal peripheral blood B cells. Moreover, we show that the levels of c-Abl protein expression correlate positively with tumor burden and disease stage, and negatively with IgV(H) mutation. We also show that STI-571, an inhibitor of c-Abl kinase activity, induces apoptosis of CLL cells with high c-Abl expression levels through a mechanism involving inhibition of nuclear factor kappaB. We conclude that overexpression of c-Abl is likely to play a pathogenetic role in CLL and that STI-571 may be of potential use in the treatment of this disease.
Lin
Ke
K
Department of Haematology, University of Liverpool, Daulby Street, Liverpool L69 3GA, United Kingdom. k.lin@liv.ac.uk
Glenn
Mark A
MA
Harris
Robert J
RJ
Duckworth
Andrew D
AD
Dennett
Sally
S
Cawley
John C
JC
Zuzel
Mirko
M
Slupsky
Joseph R
JR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism; D001549:Benzamides; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D000068877:Imatinib Mesylate; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D020033:Protein Isoforms; D016315:Proto-Oncogene Proteins c-abl / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis
D000970:Antineoplastic Agents; D001549:Benzamides; D007135:Immunoglobulin Variable Region; D016328:NF-kappa B; D010879:Piperazines; D020033:Protein Isoforms; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D051746:ZAP-70 Protein-Tyrosine Kinase