Targeting TRAF3 Downstream Signaling Pathways in B cell Neoplasms

Moore, Cynthia; Edwards, Shanique; Xie, Ping

doi:10.4172/1948-5956.1000327

Cited by 14 publications

(13 citation statements)

References 68 publications

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“…In addition, if uncontrolled, AID may target non-Ig loci in the B cell genome to induce DNA damage, contributing to lymphomagenesis (8, 50, 51). Given that mutations in TRAF2 and TRAF3 are observed in human B cell lymphomas (52, 53), our study may also provide new insights into AID regulation during lymphomagenesis.…”

Section: Discussionmentioning

confidence: 82%

TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-κB1 Activation

Woolaver

Wang

Dollin

et al. 2018

The Journal of Immunology

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Effective humoral immunity requires class switch recombination (CSR) catalyzed by activation-induced deaminase (AID). In response to T cell-dependent (TD) antigens, CSR can be induced by CD40 signaling in B cells. Tumor necrosis factor receptor associated factors 2 and 3 (TRAF2/TRAF3) function as adaptors of the CD40 signaling pathway. B cell-intrinsic TRAF2 or TRAF3 knockout mice (B-TRAF2 or B-TRAF3 KO) were previously reported to have indistinguishable phenotypes in gene expression, B cell survival and development as well as enlarged peripheral lymphoid organs. However, it remains unknown whether deficiency of B-TRAF2 or B-TRAF3 differentially affects TD humoral immune responses and CD40-induced CSR. Here, we show that B-TRAF2 is essential for optimal isotype-switching induced by in vivo TD antigen immunization or by engaging CD40 in vitro. Our data clarify the controversial role of B-TRAF3 and confirm its dispensability in CD40-induced CSR. Mechanistically, CD40-induced AID expression was markedly impaired by B-TRAF2 but not B-TRAF3 deficiency. Moreover, B-TRAF2 deficiency causes defective activation of the NF-κB1 complex in a CD40-autonomous manner, and restoring CD40-induced NF-κB1 activation in TRAF2-deficient B cells rescues AID expression and CSR. We conclude that TRAF2 is essential but TRAF3 is dispensable for TD humoral immunity and CD40-induced CSR. Our studies provide significant biological bases for optimizing treatment of B cell-associated immune disorders by targeting CD40 signaling.

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Section: Discussionmentioning

confidence: 82%

TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-κB1 Activation

Woolaver

Wang

Dollin

et al. 2018

The Journal of Immunology

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“…Interestingly however, a subgroup among the 279 cases of HNSCC cataloged in TCGA, the human papilloma virus-positive (HPV+) HNSCC tumors, has much higher frequency (22%, 8/36) of deep deletions and truncations of TRAF3 than the HPV- HNSCC tumors (Figure 1B ) ( 113 ). Notably, although not cataloged in TCGA, deletions and mutations of TRAF3 are recognized as one of the most frequent genetic alterations in a variety of B cell malignancies ( 153 ), including gastric marginal zone lymphoma (MZL, 21%) ( 154 ), multiple myeloma (MM, 17%) ( 155 , 156 ), HL (15%) ( 157 ), DLBCL (14.3%) ( 158 ), splenic MZL (10%) ( 159 ), and Waldenstrom's macroglobulinemia (WM, 5.3%) ( 160 ) (Figure 1B ). Furthermore, somatic mutations of TRAF3 are also frequently detected in human nasopharyngeal cancer (NPC, 8.6%) ( 161 ) (Figure 1B ).…”

Section: Traf3mentioning

confidence: 99%

Genetic Alterations of TRAF Proteins in Human Cancers

et al. 2018

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The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.

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“…It has been observed that pSjS patients have an increased risk to develop B cell lymphoproliferative disorders [55] and, noteworthy, BAK1 and BAX are overexpressed in diffuse large B cell lymphoma [56]; ENO1 promotes tumor proliferation in Non-Hodgkin’s Lymphomas and stimulates immunoglobulin production [57]; hnRNPL induces BCL2 overexpression in many B cell lymphomas [58] whereas TRAF3 is a tumor suppressor gene in B lymphocytes and frequently is inactivated in human B lymphoma and multiple myeloma [59]. Interestingly, we found that TRAF3 resulted in down-modulation in our patients with pSjS.…”

Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNAs Modulate Sjögren’s Syndrome Associated Gene Expression and Are Involved in the Pathogenesis of the Disease

Dolcino

Tinazzi

Vitali

et al. 2019

JCM

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Primary Sjögren’s syndrome (pSjS) is a chronic systemic autoimmune disorder, primarily affecting exocrine glands; its pathogenesis is still unclear. Long non-coding RNAs (lncRNAs) are thought to play a role in the pathogenesis of autoimmune diseases and a comprehensive analysis of lncRNAs expression in pSjS is still lacking. To this aim, the expression of more than 540,000 human transcripts, including those ascribed to more than 50,000 lncRNAs is profiled at the same time, in a cohort of 16 peripheral blood mononuclear cells PBMCs samples (eight pSjS and eight healthy subjects). A complex network analysis is carried out on the global set of molecular interactions among modulated genes and lncRNAs, leading to the identification of reliable lncRNA-miRNA-gene functional interactions. Taking this approach, a few lncRNAs are identified as targeting highly connected genes in the pSjS transcriptome, since they have a major impact on gene modulation in the disease. Such genes are involved in biological processes and molecular pathways crucial in the pathogenesis of pSjS, including immune response, B cell development and function, inflammation, apoptosis, type I and gamma interferon, epithelial cell adhesion and polarization. The identification of deregulated lncRNAs that modulate genes involved in the typical features of the disease provides insight in disease pathogenesis and opens avenues for the design of novel therapeutic strategies.

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Targeting TRAF3 Downstream Signaling Pathways in B cell Neoplasms

Cited by 14 publications

References 68 publications

TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-κB1 Activation

TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-κB1 Activation

Genetic Alterations of TRAF Proteins in Human Cancers

Long Non-Coding RNAs Modulate Sjögren’s Syndrome Associated Gene Expression and Are Involved in the Pathogenesis of the Disease

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