Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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B-Cell Activating Factor / biosynthesis
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B-Cell Activating Factor / physiology*
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B-Cell Maturation Antigen / biosynthesis
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B-Cell Maturation Antigen / immunology
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Carboxylic Acids / chemical synthesis
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Carboxylic Acids / chemistry
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Carboxylic Acids / pharmacology
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Cell Fractionation
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Cell Survival / immunology
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Flow Cytometry / methods
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Humans
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Sensitivity and Specificity
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Signal Transduction / immunology*
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
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Thiophenes / pharmacology
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Transmembrane Activator and CAML Interactor Protein / biosynthesis
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Transmembrane Activator and CAML Interactor Protein / immunology
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Tumor Necrosis Factor Ligand Superfamily Member 13 / biosynthesis
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Tumor Necrosis Factor Ligand Superfamily Member 13 / physiology*
Substances
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5-(4-fluorophenyl)-2-ureido-thiophene-3 carboxylic acid amide
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B-Cell Activating Factor
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B-Cell Maturation Antigen
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Carboxylic Acids
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NF-kappa B
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Protein Kinase Inhibitors
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TNFSF13 protein, human
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TNFSF13B protein, human
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Thiophenes
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Transmembrane Activator and CAML Interactor Protein
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Tumor Necrosis Factor Ligand Superfamily Member 13