Abstract
B-cell receptor (BCR) signaling is aberrantly activated in chronic lymphocytic leukemia (CLL). Bruton tyrosine kinase (BTK) is essential to BCR signaling and in knockout mouse models its mutation has a relatively B cell-specific phenotype. Herein, we demonstrate that BTK protein and mRNA are significantly over expressed in CLL compared with normal B cells. Although BTK is not always constitutively active in CLL cells, BCR or CD40 signaling is accompanied by effective activation of this pathway. Using the irreversible BTK inhibitor PCI-32765, we demonstrate modest apoptosis in CLL cells that is greater than that observed in normal B cells. No influence of PCI-32765 on T-cell survival is observed. Treatment of CD40 or BCR activated CLL cells with PCI-32765 results in inhibition of BTK tyrosine phosphorylation and also effectively abrogates downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. In addition, PCI-32765 inhibits activation-induced proliferation of CLL cells in vitro, and effectively blocks survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement, and stromal cell contact. Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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B-Cell Activating Factor / genetics
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B-Cell Activating Factor / metabolism
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B-Lymphocytes / enzymology
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CD40 Ligand / genetics
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CD40 Ligand / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cell Survival / genetics
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Drug Screening Assays, Antitumor / methods
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Female
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Gene Expression Regulation, Enzymologic / drug effects*
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Gene Expression Regulation, Enzymologic / genetics
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Gene Expression Regulation, Leukemic / drug effects*
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Gene Expression Regulation, Leukemic / genetics
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Humans
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
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Leukemia, Lymphocytic, Chronic, B-Cell / enzymology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Male
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Mice
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Piperidines
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / biosynthesis
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Protein-Tyrosine Kinases / genetics
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Pyrazoles / pharmacology*
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Pyrimidines / pharmacology*
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Receptors, Antigen, B-Cell / genetics
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Receptors, Antigen, B-Cell / metabolism
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T-Lymphocytes / enzymology
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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B-Cell Activating Factor
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IL4 protein, human
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IL6 protein, human
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Interleukin-6
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NF-kappa B
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Neoplasm Proteins
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Piperidines
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Pyrazoles
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Pyrimidines
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Receptors, Antigen, B-Cell
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TNFSF13B protein, human
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Tumor Necrosis Factor-alpha
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CD40 Ligand
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ibrutinib
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Interleukin-4
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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Btk protein, mouse
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Adenine