Bortezomib induces different apoptotic rates in B-CLL cells according to IgVH and BCL-6 mutations.
BACKGROUND
B-cell chronic lymphocytic leukemia (B-CLL) is a remarkably heterogeneous disorder. Some patients have an indolent disease whereas others undergo a more agressive presentation needing treatment. New therapeutics approaches are necessary for the treatment of B-CLL. Bortezomib (Btz), is a proteasome inhibitor, currently undergoing clinical trials whose function, at least in part, by stabilizing the IkappaBalpha protein and inhibiting NFkappaB activation.


OBJECTIVE
The objective of this work was to study the effects of Btz on isolated human B-CLL cells, in vitro, and to correlate the differential rates of apoptosis induction with biological variables.


METHODS
31 B-CLL samples, from patients in stage A of Binet were used for this study, and the apoptotic effect of Btz on these cells was measured.


RESULTS
Our data show that Btz treatment of B-CLL cells induces apoptosis in a time and dose-dependent manner. The apoptosis induction is mediated in part by inhibition of NFkappaB and is dependent on caspases activation. Interesting, in IgVH mutated cells, Btz have statistically significant differences in their in vitro activity on B-CLL cells according to their BCL-6 mutational status.


CONCLUSIONS
Btz is a promising pharmacologic agent for the treatment of B-CLL, but its efficacy seems to be related to IgVH and BCL-6 mutational status, therefore, it could be interesting to further investigate the mechanisms involved in the different behavior of the cells in response to apoptosis induction by this drug.
Jantus-Lewintre
Eloisa
E
Hospital Clínico Universitario de Valencia. Valencia. Spain. ejantus@cipf.es
Sarsotti
Elena
E
Terol
María José
MJ
Benet
Isabel
I
García-Conde
Javier
J
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D020672:I-kappa B Proteins / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000096:biosynthesis / Q000235:genetics
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D001897:Boronic Acids; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D020672:I-kappa B Proteins; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D016328:NF-kappa B; D009363:Neoplasm Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D051560:Proto-Oncogene Proteins c-bcl-6; D011719:Pyrazines; D013450:Sulfones; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000069286:Bortezomib; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; D051550:I-kappa B Kinase; D051997:ADP-ribosyl Cyclase 1; D020169:Caspases