Abstract
Chronic lymphocytic leukemia (CLL) B cells that express unmutated immunoglobulin heavy-chain variable region genes (IgV(H)) generally express ZAP-70, in contrast to normal B cells or most CLL cases with mutated IgV(H). Following IgM ligation, ZAP-70+ CLL cells had significantly higher levels of phosphorylated p72(Syk), BLNK, and phospholipase-Cgamma (PLCgamma) and had greater[Ca2+]i flux than did ZAP-70-negative CLL cases, including unusual ZAP-70-negative cases with unmutated IgV(H). IgM ligation of ZAP-70-negative CLL B cells infected with an adenovirus vector encoding ZAP-70 induced significantly greater levels of phosphorylated p72(Syk), BLNK, and PLCgamma and had greater[Ca2+]i flux than did similarly stimulated, noninfected CLL cells or CLL cells infected with a control adenovirus vector. We conclude that expression of ZAP-70 in CLL allows for more effective IgM signaling in CLL B cells, a feature that could contribute to the relatively aggressive clinical behavior generally associated with CLL cells that express unmutated IgV(H).
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Carrier Proteins / metabolism
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Enzyme Precursors / metabolism
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Humans
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Immunoglobulin Heavy Chains
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Immunoglobulin M / physiology*
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Immunoglobulin Variable Region
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Intracellular Signaling Peptides and Proteins
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
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Phospholipase C gamma
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Phosphoproteins / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology*
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Signal Transduction*
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Syk Kinase
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Type C Phospholipases / metabolism
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Adaptor Proteins, Signal Transducing
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B cell linker protein
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Carrier Proteins
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Enzyme Precursors
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Immunoglobulin Heavy Chains
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Immunoglobulin M
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Immunoglobulin Variable Region
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
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Type C Phospholipases
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Phospholipase C gamma