Phosphorylation promotes activation-induced cytidine deaminase activity at the Myc oncogene

Molecular & Cellular Oncology

2018

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mentioning

confidence: 78%

mentioning

confidence: 82%

mentioning

confidence: 97%

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Targeting mutagenesis in B cells: Phosphorylation goes beyond AID association

Molecular & Cellular Oncology

2018

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“…Naïve B cells were purified from spleens of wild-type and Wwox KO 16–17 day-old mice (38, 39) by anti-CD43 bead depletion (Miltenyi Biotec). Cells were cultured in LPS (25 μg/ml, Sigma-Aldrich) and IL-4 (5 ng/ml, RD) for 72 h. To determine CSR to IgG1, cultured B cells were stained with anti-IgG1 antibodies and flow cytometric analysis of surface Ig expression was performed on a LSRFortessa (BD) with scatter gating and propidium iodide staining to exclude dead cells (40). Results were analyzed with FlowJo (Tree Star) and averages were obtained from triplicate cultures of six individual spleens in four independent experiments.…”

Section: Methodsmentioning

confidence: 99%

Wwox Deletion in Mouse B Cells Leads to Genomic Instability, Neoplastic Transformation, and Monoclonal Gammopathies

Kil

et al. 2019

Front. Oncol.

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WWOX (WW domain containing oxidoreductase) expression loss is common in various cancers and characteristic of poor prognosis. Deletions, translocations, and loss of expression affecting the WWOX gene are a common feature of various B cell neoplasms such as certain B cell lymphomas and multiple myeloma. However, the role of this common abnormality in B cell tumor initiation and/or progression has not been defined. In this study, we conditionally deleted Wwox early in B cell development by means of breeding Cd19-Cre transgenic mice crossed to Wwox floxed mice ( Cd19 Wwox KO ). We observed a significant reduced survival in Cd19 Wwox KO mice and the development of B cell neoplasms including B cell lymphomas, plasma cell neoplasias characterized by increased numbers of CD138+ populations as well as monoclonal gammopathies detected by serum protein electrophoresis. To investigate whether Wwox loss could play a role in genomic instability, we analyzed DNA repair functions during immunoglobulin class switch joining between DNA segments in antibody genes. While class switch recombination (CSR) was only slightly impaired, Wwox deficiency resulted in a dramatic shift of double strand break (DSB) repair from normal classical-NHEJ toward the microhomology-mediated alternative-NHEJ pathway, a pathway associated with chromosome translocations and genome instability. Consistent with this, Wwox deficiency resulted in a marked increase of spontaneous translocations during CSR. This work defines for the first time a role for Wwox for maintaining B cell genome stability during a process that can promote neoplastic transformation and monoclonal gammopathies.

“…AID mis-expression induces genome instability and cancer [ 59 ]. Within B cells, deregulation of AID protein levels [ 60 , 61 ] or post-translational modifications that control activity [ 62 , 63 ] result in genome instability and chromosome translocations. Therefore, viral factors that induce AID and RAG1/2 or disrupt the regulatory mechanism of these proteins could produce oncogenic lesions that contribute to associated lymphomas.…”

Section: Germinal Center Processes That Shape B Cell Evolution Andmentioning

confidence: 99%

Dangerous Liaisons: Gammaherpesvirus Subversion of the Immunoglobulin Repertoire

Zelazowska

Krug

2020

Viruses

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A common biologic property of the gammaherpesviruses Epstein–Barr Virus and Kaposi sarcoma herpesvirus is their use of B lymphocytes as a reservoir of latency in healthy individuals that can undergo oncogenic transformation later in life. Gammaherpesviruses (GHVs) employ an impressive arsenal of proteins and non-coding RNAs to reprogram lymphocytes for proliferative expansion. Within lymphoid tissues, the germinal center (GC) reaction is a hub of B cell proliferation and death. The goal of a GC is to generate and then select for a pool of immunoglobulin (Ig) genes that will provide a protective humoral adaptive immune response. B cells infected with GHVs are detected in GCs and bear the hallmark signatures of the mutagenic processes of somatic hypermutation and isotype class switching of the Ig genes. However, data also supports extrafollicular B cells as a reservoir engaged by GHVs. Next-generation sequencing technologies provide unprecedented detail of the Ig sequence that informs the natural history of infection at the single cell level. Here, we review recent reports from human and murine GHV systems that identify striking differences in the immunoglobulin repertoire of infected B cells compared to their uninfected counterparts. Implications for virus biology, GHV-associated cancers, and host immune dysfunction will be discussed.