Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection of human B cells with Epstein-Barr virus (EBV) was seen to result in activation-induced cytidine deaminase (AID) and polymerase-eta (pol-eta) gene expression. AID and pol-eta are cellular gene products that play central roles in the DNA-modifying processes involved in immunoglobulin gene class switch recombination and somatic hypermutation. Errors in these processes can result in oncogene mutation/translocation, thereby contributing to lymphomagenesis. It was seen that EBV infected, AID, and pol-eta expressing B cells accumulated mutations in cellular proto-oncogenes (BCL-6 and p53) that are known to be involved in the genesis of B cell lymphoma. The nature of the mutations seen in these oncogenes was consistent with the known activity of AID and pol-eta. These findings indicate that EBV induced AID and pol-eta expression, and that this was associated with oncogene mutation, providing a novel means by which EBV infection of B cells may contribute to lymphomagenesis.
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PMID:Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations. 1673 63

The transit of T cell-activated B cells through the germinal center (GC) is controlled by sequential activation and repression of key transcription factors, executing the pre- and post-GC B cell program. B cell lymphoma (BCL) 6 and IFN regulatory factor (IRF) 8 are necessary for GC formation and for its molecular activity in Pax5+PU.1+ B cells. IRF4, which is highly expressed in BCL6- GC B cells, is necessary for class switch recombination and the plasma cell differentiation at exit from the GC. In this study, we show at the single-cell level broad coexpression of IRF4 with BCL6, Pax5, IRF8, and PU.1 in pre- and post-GC B cells in human and mouse. IRF4 is down-regulated in BCL6+ human GC founder cells (IgD+CD38+), is absent in GC centroblasts, and is re-expressed in positive regulatory domain 1-positive centrocytes, which are negative for all the B cell transcription factors. Activated (CD30+) and activation-induced cytidine deaminase-positive extrafollicular blasts coexpress Pax5 and IRF4. PU.1-negative plasma cells and CD30+ blasts uniquely display the conformational epitope of IRF4 recognized by the MUM1 Ab, an epitope that is absent from any other IRF4+PU.1+ lymphoid and hemopoietic subsets. Low grade B cell lymphomas, representing the malignant counterpart of pre- and post-GC B cells, accordingly express IRF4. However, a fraction of BCL6+ diffuse large B cell lymphomas express IRF4 bearing the MUM1 epitope, indicative of a posttranscriptional modification of IRF4 not seen in the normal counterpart.
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PMID:Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance. 1708 8

Recently, a novel mechanism introducing genetic instability, termed aberrant somatic hypermutation (ASHM), has been described in diffuse large B-cell lymphoma. To further investigate whether ASHM also occurs in mucosa-associated lymphoid tissue type (MALT) lymphoma, we studied the mutation profile of PIM1, PAX5, RhoH/TTF, and c-MYC in 17 MALT lymphomas and 17 extranodal diffuse large B-cell lymphomas (DLBCLs) still exhibiting a low-grade MALT lymphoma component (transformed MALT lymphoma). Mutations in one or more genes were detected in 13 (76.5%) of 17 cases of MALT lymphomas and in all of 17 (100%) cases of extranodal DLBCL. A total of 100 sequence variants were found in 30 of 34 cases, 28 in the MALT lymphomas and 72 in extranodal DLBCL. Further, in PIM1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. Expression levels of activation-induced cytidine deaminase (AID), an enzyme essential for somatic hypermutation (SHM), was associated with the mutational load. These data indicate that aberrant SHM is associated with extranodal DLBCL and MALT lymphoma, likewise. By mutating regulatory and coding sequences of the targeted genes, ASHM may represent a major contributor to their pathogenesis.
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PMID:MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation. 1719 34

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (Smu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sgamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing Smu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Smu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB.
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PMID:Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. 1735 67

A hallmark of mature B-cell lymphomas is reciprocal chromosomal translocations involving the Ig locus and a proto-oncogene, which usually result in the deregulated, constitutive expression of the translocated gene. In addition to such translocations, proto-oncogenes are frequently hypermutated in germinal center (GC)-derived B-cell lymphomas. Although aberrant, mistargeted class switch recombination (CSR) and somatic hypermutation (SHM) events have long been suspected of causing chromosomal translocations and mutations in oncogenes, and thus of playing a critical role in the pathogenesis of most B-cell lymphomas, the molecular basis for such deregulation of CSR and SHM is only beginning to be elucidated by recent genetic approaches. The tumorigenic ability of activation-induced cytidine deaminase (AID), a key enzyme that initiates CSR and SHM, was revealed in studies on AID transgenic mice. In addition, experiments with AID-deficient mice clearly showed that AID is required not only for the c-myc/IgH translocation but also for the malignant progression of translocation-bearing lymphoma precursor cells, probably by introducing additional genetic hits. Normally, AID expression is only transiently and specifically induced in activated B cells in GCs. However, recent studies indicate that AID can be induced directly in B cells outside the GCs by various pathogens, including transforming viruses associated with human malignancies. Indeed, AID expression is not restricted to GC-derived B-cell lymphomas, but is also found in other types of B-cell lymphoma and even in nonlymphoid tumors, suggesting that ectopically expressed AID is involved in tumorigenesis and disease progression in a wide variety of cell types.
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PMID:Role of AID in tumorigenesis. 1756 Feb 77

Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.
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PMID:AID is required for germinal center-derived lymphomagenesis. 1806 64

Non-Hodgkin's B cell lymphoma (NHL) is a common cancer in HIV infection. Many NHL are thought to result from errors in class switch recombination and/or somatic hypermutation, processes that occur in germinal center B cells, and require the activity of activation induced cytidine deaminase (AID). Since NHL is a common cancer in HIV infection, and expression of AID could contribute to the development of NHL, we hypothesized that AID expression would be elevated in those who went on to develop AIDS-associated NHL (AIDS-NHL). AID mRNA levels were measured by TaqMan RT-PCR in peripheral blood mononuclear cells, obtained prior to AIDS-NHL diagnosis, from 16 HIV-infected subjects who developed AIDS-NHL, and from control subjects (AIDS but no NHL, and HIV-negative subjects). PBMC AID expression was markedly elevated in those who developed AIDS-NHL, when compared to AIDS and HIV-negative controls. Additionally, AID expression was seen to differ depending on NHL subtype, with the highest levels of expression seen in those who developed Burkitt's lymphoma.
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PMID:Elevated expression of activation induced cytidine deaminase in peripheral blood mononuclear cells precedes AIDS-NHL diagnosis. 1809 Feb 74

Somatic hypermutation of immunoglobulin genes and class switch recombination are pivotal processes in the germinal center (GC) reaction and have been implicated in the development of malignant B-cell lymphoma. Both processes require the enzyme activation-induced cytidine deaminase (AID). Expression of AID is largely restricted to GC B cells and B cells that undergo class switch recombination outside the GC. AID is also expressed in many B-cell lymphomas. This study investigates the expression of AID of malignant lymphomas infiltrating the bone marrow. Bone marrow trephines (n=130) with infiltration of Hodgkin lymphoma and non-Hodgkin lymphoma of B cell and T-cell type and trephines with reactive lymphoid follicles (n=16) were analyzed immunohistochemically for AID protein. AID is expressed in bone marrow infiltrates of malignant lymphomas. AID was generally detected in lymphomas of GC origin. Tumor cells of hairy cell leukemia are mostly AID. There is apparently no different expression of AID found in bone marrow infiltrates of malignant lymphomas compared with a control group with nodal malignant lymphoma infiltrates (n=105). These results suggest that the expression pattern of AID in lymphoma infiltrates in the bone marrow reflects that of extramedullary lymphoma infiltrates.
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PMID:Expression of activation-induced cytidine deaminase in malignant lymphomas infiltrating the bone marrow. 1877 14

To determine a possible role of aberrant somatic hypermutation (ASHM) in the pathogenesis of thyroid lymphoma (TL), mutational status of genes affected by ASHM, including c-MYC, PIM-1, PAX-5 and RhoH/TTF, was analyzed. Tumor specimens from 33 patients with thyroid B-cell lymphoma and 14 with chronic lymphocytic thyroiditis (CLTH), an autoimmune thyroiditis known to provide a basis for TL development, was examined. Mutations of at least one of these genes was detected in 16 of 33 (48.5%) patients with TL and in 2 of 14 (14.3%) CLTH. Occurrence of ASHM in PIM-1, RhoH/TTF, and c-MYC was a constant finding in follicular lymphoma (FL) (all of 11 cases) but not so frequent in diffuse large B-cell lymphoma (DLBCL) (4 (33.3%) of 12 cases) and Marginal zone B-cell lymphoma (MZBCL) (1 (10.0%) of 10 cases). ASHM activity is ongoing in most of FL and DLBCL because intraclonal variants were found. FL was also unique in its lower expression level of activation-induced cytidine deaminase, a main player in DNA-modifying processes during SHM, compare to DLBCL and MZBCL.
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PMID:Aberrant somatic hypermutations in thyroid lymphomas. 1901 31

B-cell chronic lymphocytic leukemia (CLL) is an incurable disease with a highly variable clinical course. A proportion of patients eventually progress to a higher stage of malignancy. A recent association has been observed between the presence of aberrant somatic hypermutations in leukemic cells (hypermutations occurring outside of the immunoglobulin locus) and the transformation to a diffuse large B-cell lymphoma or prolymphocytic leukemia. In this study, we report on the rarely observed blastic transformation in a CLL patient who had previously been shown to harbor aberrant somatic hypermutations in the TP53 tumor-suppressor gene (Mol Immunol 2008;45:1525-29). The enzyme responsible, the activation-induced cytidine deaminase, was still active within the transformation, as evidenced by the ongoing class-switch recombination of cytoplasmic immunoglobulins. The transformation was accompanied by a complete p53 inactivation, as well as complex karyotype changes including prominent amplification of MYCN oncogene. Our case-study supports the view that the aberrant somatic hypermutation is associated with transformation of CLL to a more aggressive malignancy.
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PMID:Inactivation of p53 and amplification of MYCN gene in a terminal lymphoblastic relapse in a chronic lymphocytic leukemia patient. 1916 13


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