Abstract
The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation.
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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Amino Acid Sequence
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Amyloidosis / complications
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Amyloidosis / pathology*
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Animals
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Antigens, Ly / metabolism
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Cell Extracts
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Disease Models, Animal
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Enzyme Activation
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Germinal Center / metabolism*
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Germinal Center / pathology
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Humans
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Hypergammaglobulinemia / pathology
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Hyperplasia
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Intracellular Signaling Peptides and Proteins / metabolism*
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Intracellular Space / metabolism
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Kaplan-Meier Estimate
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Lymphoma, B-Cell / complications
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Lymphoma, B-Cell / enzymology*
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Lymphoma, B-Cell / pathology*
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Membrane Proteins / metabolism
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Mice
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Microfilament Proteins
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Molecular Sequence Data
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Neoplasm Proteins / metabolism*
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Protein Binding
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Protein-Tyrosine Kinases / metabolism*
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RNA, Small Interfering / metabolism
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Receptors, Antigen, B-Cell / metabolism*
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Serum Amyloid A Protein / chemistry
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Serum Amyloid A Protein / metabolism
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Signal Transduction
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Spleen / metabolism
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Spleen / pathology
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Syk Kinase
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Transcriptome / genetics
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rhoA GTP-Binding Protein / metabolism
Substances
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Antigens, Ly
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Cell Extracts
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GCSAM protein, human
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Intracellular Signaling Peptides and Proteins
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Ly6a protein, mouse
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Membrane Proteins
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Microfilament Proteins
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Neoplasm Proteins
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RNA, Small Interfering
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Receptors, Antigen, B-Cell
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Saa2 protein, mouse
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Serum Amyloid A Protein
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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rhoA GTP-Binding Protein