Abstract
During an immune response, B cells undergo rapid proliferation and activation-induced cytidine deaminase (AID)-dependent remodeling of immunoglobulin (IG) genes within germinal centers (GCs) to generate memory B and plasma cells. Unfortunately, the genotoxic stress associated with the GC reaction also promotes most B cell malignancies. Here, we report that exogenous and intrinsic AID-induced DNA strand breaks activate ATM, which signals through an LKB1 intermediate to inactivate CRTC2, a transcriptional coactivator of CREB. Using genome-wide location analysis, we determined that CRTC2 inactivation unexpectedly represses a genetic program that controls GC B cell proliferation, self-renewal, and differentiation while opposing lymphomagenesis. Inhibition of this pathway results in increased GC B cell proliferation, reduced antibody secretion, and impaired terminal differentiation. Multiple distinct pathway disruptions were also identified in human GC B cell lymphoma patient samples. Combined, our data show that CRTC2 inactivation, via physiologic DNA damage response signaling, promotes B cell differentiation in response to genotoxic stress.
Copyright © 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AMP-Activated Protein Kinase Kinases
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / radiation effects
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Animals
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Ataxia Telangiectasia Mutated Proteins
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B-Lymphocytes / cytology*
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology
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B-Lymphocytes / metabolism
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B-Lymphocytes / radiation effects
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Differentiation / drug effects
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Cell Differentiation / immunology*
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Cell Differentiation / radiation effects
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Cell Line, Tumor
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Cytidine Deaminase / genetics*
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DNA Breaks, Double-Stranded / drug effects
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DNA Breaks, Double-Stranded / radiation effects
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DNA Damage / drug effects
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DNA Damage / immunology*
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DNA Damage / radiation effects
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression / drug effects
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Gene Expression / immunology
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Gene Expression / radiation effects
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Gene Expression Regulation / immunology
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Germinal Center / cytology
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Humans
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Immunoglobulin Class Switching / physiology
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism
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Metformin / pharmacology
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Mice
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Mice, Knockout
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Phosphorylation / drug effects
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Phosphorylation / radiation effects
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Plasma Cells / cytology
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Plasma Cells / immunology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins / genetics
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / immunology
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Signal Transduction / radiation effects
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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CRTC2 protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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Proto-Oncogene Proteins
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TCL1A protein, human
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Transcription Factors
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Tumor Suppressor Proteins
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Metformin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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STK11 protein, human
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AMP-Activated Protein Kinase Kinases
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase