BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-kappaB pathway.
Chronic lymphocytic leukemia (CLL) B cells express BR3, the specific receptor for the B cell-activating factor of tumor necrosis factor family (BAFF). CLL cells also express 2 other receptors for BAFF, namely B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI), which also bind a proliferation-inducing ligand (APRIL). We found that signaling through BR3, but not BCMA or TACI, activated the alternative nuclear factor of kappa B (NF-kappaB) pathway in CLL cells, whereas signaling through BCMA/TACI induced activation of the canonical NF-kappaB pathway. Blocking BR3 did not inhibit the capacity of BAFF to support CLL cell survival in vitro. On the other hand, specifically blocking the canonical NF-kappaB pathway with UTC, an inhibitor of IkappaB kinase beta (IKKbeta), or transfection of CLL cells with the IkappaBalpha super-repressor, blocked the capacity of BAFF and APRIL to promote CLL cell survival in vitro. This contrasts what is found with normal blood B cells, which apparently depend on activation of the alternative NF-kappaB pathway for BAFF-enhanced survival. These findings suggest that inhibitors of protein kinase IKKbeta, which is required for activation of the canonical NF-kappaB pathway, might have a therapeutic role in this disease.
Endo
Tomoyuki
T
Moores Cancer Center and Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0820, USA.
Nishio
Mitsufumi
M
Enzler
Thomas
T
Cottam
Howard B
HB
Fukuda
Tetsuya
T
James
Danelle F
DF
Karin
Michael
M
Kipps
Thomas J
TJ
D053264:B-Cell Activating Factor / Q000096:biosynthesis / Q000502:physiology*; D053301:B-Cell Maturation Antigen / Q000096:biosynthesis / Q000276:immunology; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002458:Cell Fractionation; D002470:Cell Survival / Q000276:immunology; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000276:immunology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000096:biosynthesis / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000096:biosynthesis / Q000502:physiology*
C522203:5-(4-fluorophenyl)-2-ureido-thiophene-3 carboxylic acid amide; D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D002264:Carboxylic Acids; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C114631:TNFSF13 protein, human; C505719:TNFSF13B protein, human; D013876:Thiophenes; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13