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)

The cbl oncogene was first identified as part of a transforming retrovirus which arose in a mouse pre-B cell lymphoma. Its protein product, p120cbl, is cytoplasmic and has several distinctive domains including a highly basic region, a RING finger motif and a large proline-rich domain. A mutation to cbl in the 70Z/3 pre-B cell lymphoma produces an oncogenic protein which exhibits a marked enhancement of tyrosine phosphorylation. Parallel studies have demonstrated that p120cbl is a substrate of protein Tyrosine kinases activated by engagement of the T cell antigen receptor and that cbl is phosphorylated by oncogenic forms of the Abl tyrosine kinase. These studies also demonstrated a constitutive association between cbl and the SHS domains of the Grb2 and Nck adaptor proteins in a range of haemopoietic cell lines. More recently it has been found that cbl is rapidly phosphorylated following stimulation of the EGF receptor, Fcy receptor, c-Kit receptor and CSF-1 receptor. A genetic analysis in Caenorhabditis elegans has identified a cbl homologue, called sli-1, that negatively regulates the LET-23 tyrosine kinase receptor. These characteristics indicate a central role for cbl in the regulation of intracellular signals that are mediated by growth factors and antigenic stimuli which activate protein tyrosine kinases.
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PMID:The cbl oncogene: a novel substrate of protein tyrosine kinases. 877 Mar 64

Primary effusion lymphoma (PEL) is a distinct clinicopathologic entity associated with Kaposi's sarcoma-associated herpes virus (KSHV). Several cytokines, including interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) may be important for survival of KS cells. However, little is known about the interaction of cytokines with KSHV-infected lymphocytes from PEL. Therefore, we investigated what cytokines were produced by KSHV-infected PEL cell lines (KS-1, BC-1, BC-2), what cytokine receptors were expressed by these cells, what response these cells had to selected cytokines, and what was the effect of IL-6 antisense phosphorothioated oligonucleotides. Reverse transcriptase-polymerase chain reaction (RT-PCR) and protein studies showed that these three cell lines produced IL-10, IL-6, and the receptors for IL-6. The granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1beta, IL-8, IL-12, bFGF, PDGF, and c-kit transcripts were not detected in the cell lines. High levels (0.7 to 5 ng/mL/10(6) cells/48 hours) of IL-6 protein were consistently detected in supernatants of the cell lines by enzyme-linked immunosorbent assay (ELISA) tests. In clonogenic assays, interferon-alpha (IFN-alpha) and IFN-gamma suppressed the clonal growth of the PEL cells, but GM-CSF, IL-4, IL-6, IL-8, IL-10, and oncostatin M did not change it. We examined for several autocrine loops that have been suggested to occur in KS. Experiments using antisense oligonucleotides showed that the clonal growth of KS-1 and BC-1 was nearly 100% inhibited by IL-6 antisense oligonucleotides (10 micromol/L), but not at all by either oligonucleotides (</=10 micromol/L) to IL-6 sense, IL-6 scrambled, viral IL-6 (vIL-6) antisense, or IL-10 antisense. Furthermore, the IL-6 antisense oligonucleotides had no effect on two B-cell lymphoma cell lines, which were not infected with KSHV. Addition of IL-6 antibody did not inhibit clonal growth of any of the cell lines. Taken together, we have defined the cytokines and their receptors expressed on PEL cells and have found that these cells synthesized IL-6 and IL-6 receptors; interruption of this pathway by IL-6 antisense oligonucleotides specifically prevented the growth of these cells. These findings will offer potential new therapeutic strategies for PEL.
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PMID:Mechanisms of growth control of Kaposi's sarcoma-associated herpes virus-associated primary effusion lymphoma cells. 951 48

The first case of B-cell lymphoma of brain in a patient with myelodysplastic syndrome (MDS) was reported. A 68-year-old man was admitted because of anemia, fever, and thrombocytopenia and was diagnosed as having MDS (refractory anemia with excess of blasts) on the basis of the findings of bone marrow aspiration and chromosomal analysis. The patient was followed up without chemotherapy, but a brain tumor appeared after 3 years. Histologic and immunohistologic examinations revealed diffuse large B-cell lymphoma. Mutations of the c-kit proto-oncogene (stem cell factor receptor) and the p53 tumor-suppressor gene were examined in the MDS lesion and malignant lymphoma (ML) by the polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) method followed by direct sequencing. The p53 mutation was not found in either MDS or ML, but a nonsense mutation (Try-557 --> stop) in exon 11 of the c-kit, which might lead to dysfunction of tyrosine kinase activity, was detected in MDS. This is the first report of c-kit mutation in MDS. Epstein-Barr virus (EBV) genome was demonstrated in the nucleus of brain ML cells by in situ hybridization with EBV-encoded RNA-1 probe. Immunohistochemistry showed that the tumor cells expressed latent infection gene products, including EBV nuclear antigen-2 and latent membrane protein-1. This pattern of latent gene expression was Lat III, which is usually found in malignant lymphomas developing in immunocompromised hosts. These findings suggest that a profound pancytopenia in MDS resulted in an immunodeficient condition, after which EBV-positive B-cell lymphoma of brain developed.
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PMID:Epstein-Barr virus associated B-cell lymphoma of brain developing in myelodysplastic syndrome with c-kit mutation (Try-557 -->stop). 1107 41

Little is known about the embryonic factors that regulate the size of the primordial follicle endowment at birth. A few studies suggest that members of the B-cell lymphoma/leukemia-2 (bcl-2) family of protooncogenes may be important determinants. Thus, the purpose of this study was to test whether bcl-2 regulates the size of the primordial follicle pool at birth. To test this hypothesis, three lines of transgenic mice (c-kit/bcl-2 mice) were generated that overexpress human bcl-2 in an effort to reduce prenatal oocyte loss. The overexpression was targeted to the ovary and appropriate embryonic time period with the use of a 4.8-kilobase c-kit promoter. This promoter provided two to three times more expression of bcl-2 in the ovaries with minimal or no overexpression in most nongonadal tissues. On Postnatal Days 8-60, ovaries were collected from homozygous c-kit/bcl-2 and nontransgenic littermates (controls) and processed for histological evaluation of follicle numbers. All lines of c-kit/bcl-2 mice were born with significantly more primordial follicles than control mice (P < or = 0.05). By Postnatal Days 30-60, however, there were no significant differences in follicle numbers between c-kit/bcl-2 and control mice. These results indicate that bcl-2 overexpression increases the number of primordial follicles at birth, but that the surfeit of primordial follicles is not maintained in postnatal life. These data suggest that it is possible that the ovary may contain a census mechanism by which excess numbers of primordial follicles at birth are detected and removed from the ovary by adulthood.
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PMID:Effect of bcl-2 on the primordial follicle endowment in the mouse ovary. 1125 62

Gastric lymphoma and gastrointestinal stromal tumours (GISTs) are rare malignancies of the upper gastrointestinal tract. The most common gastric lymphoma are low-grade marginal zone B-cell lymphoma (MZBCL) of MALT type. They develop as a consequence of chronic Helicobacter pylori infection, the histological hallmark are lymphoepithelial lesions. In early stages of disease, H. pylori eradication alone may lead to complete lymphoma remission in up to 75% of cases. Nonresponder or locally advanced lymphoma should be treated with radiation therapy. Advanced lymphoma may be treated with the nucleoside analogon cladribine within clinical trials. Based on clinical and novel molecular markers a risk stratification and a prediction of response to therapy might be possible in the future. GISTs are mesenchymal tumours that characteristically express CD-117 (c-kit). They are mostly localized in the upper gastrointestinal tract and are frequently diagnosed in an advanced stage. Conventional chemotherapy is ineffective. For resectable non-metastasized tumours surgical therapy is the treatment of choice. Imatinib is the first and so far only effective systemic therapy which is presently indicated in irresectable or metastasized GISTs. More than 80% of patients respond to imatinib therapy either with partial remission or stable disease. FDG-PET plays an important role in the early prediction of response to imatinib therapy. The optimal dosage and duration of treatment and the role of imatinib as adjuvant or neo-adjuvant therapy for GISTs remains to be defined.
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PMID:[Gastric MALT lymphoma and gastrointestinal stromal tumors (GIST)]. 1567 65

Nasal natural killer/T-cell lymphoma (N-NK/T-L) is prevalent in China. To further characterize this neoplasm, 36 cases of N-NK/T-L from 304 cases of malignant lymphomas in the north China area were investigated by histopathology, immunophenotyping, and genomic analysis of c-kit, in comparison with 11 cases of B-cell lymphoma (BCL) at the same region and 5 cases of nodal peripheral T-cell lymphoma (PTCL) (unspecified). Histopathologically, N-NK/T-L was characterized by coagulative necrosis, inflammatory background, and angiodestructive growth pattern. In 36 cases of N-NK/T-L, 27 cases (75.0%) were stained for CD45RO and 25 (72.2%) for CD3epsilon. Thirty cases (83.3%) were positive for T-cell intracellular antigen-1, 22 (61.1%) for granzyme B, 18 (50.0%) for CD56, and 11 (30.6%) for CD30, whereas none was positive for CD117. All 5 cases of PTCL displayed positive staining for CD45RO and T-cell intracellular antigen-1, 3 cases for CD3epsilon, but only 1 case for granzyme B. All 11 BCLs presented positive staining for CD20 and CD79a but negative for other antibodies. A significant relationship was observed between neoplastic cells pleomorphism and granzyme B expression (P < .05). Despite the fact that all cases were negative for CD117 staining, genomic sequences of c-kit 11 and exon 17 sequencing showed that 8 (26%) of 31 cases N-NK/T-L proved to contain genomic mutations, including 4 cases in exon 11 and 4 in exon 17. For the control group, only 1 (9%) of 11 BCLs and 1 (20%) of 5 cases of PTCL were detected to harbor mutations in exon 11. All mutations detected in 3 groups were missense by base substitution, and codes 571, 572, and 821 were hot spots. The results suggested that, in addition to histological features and routine immunophenotyping, granzyme B expression should be a more reliable marker in correct diagnosis of N-NK/T-L, and genetic analysis of c-kit mutation should be helpful in the diagnosis of this tumor.
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PMID:Immunohistochemical and genetic analysis of Chinese nasal natural killer/T-cell lymphomas. 1636 Apr 16

Sinonasal lymphomas comprise NK/T-cell (NKTCL) type and B-cell type with unique geographical development. In this study, mutations of p53, K-ras, c-kit, beta-catenin, and bak gene were analyzed using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) followed by direct sequencing in 41 sinonasal lymphomas (27 NKTCL and 14 B-cell type) from Indonesia. In situ hybridization study with EBER-1 probe revealed that 85% of NKTCL cases were EBV positive, but none of B-cell type was EBV positive. Frequency of mutations in p53, K-ras, c-kit, beta-catenin, and bak gene was 62.9%, 0%, 11.1%, 18.5%, and 25.9%, respectively, in NKTCL, and 71.4%, 0%, 23.1%, 21.4%, and 57.1%, respectively, in B-cell cases, showing that mutation frequency in all genes was higher in B-cell than in NKTCL cases. These findings suggest that gene mutations might be the driving-force for B-cell lymphoma, whereas combined EBV infection and gene mutations contribute to NKTCL development in Indonesia.
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PMID:Gene mutation analysis of sinonasal lymphomas in Indonesia. 1659 95

To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34(+) cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.
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PMID:Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma. 1736 63

A biomarker is defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic/pharmacodynamic responses to a therapeutic intervention". Various assays, including immunohistochemistry, gene constitution such as amplification, mutation, and rearrangement, gene and protein expression analysis such as single gene or protein expression, exhaustive analysis and gene or protein signature and single nucleotide polymorphism have been used to identify biomarkers in recent years. No therapeutic effects have yet been predicted based on the results of such exhaustive gene analysis because of low reproducibility although some correlate with the prognosis of patients. Biomarkers such as HER2 for breast cancer or EGFR mutation for lung cancer and KRAS mutation in colon cancer have contributed to identify a patient population that might show a good and bad treatment response, respectively. On the other hand, other biomarkers such as bcr-abl, c-kit gene mutation and CD20 expression, which are positive for CML, GIST and B cell lymphoma, respectively, have crucial biological significance but have not necessarily been used for practical clinical screening since pathological diagnosis coincide with finding of biomarkers. Hence, much work remains to be done in many areas of biomarker research.
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PMID:Critical comments for roles of biomarkers in the diagnosis and treatment of cancer. 2165 49

Nilotinib, a second-generation tyrosine kinase inhibitor, has been recently approved for the treatment for chronic myeloid leukaemia. The objective of this study was to explore the potential effects of clinically relevant doses of nilotinib against acetaminophen (APAP)-induced hepatotoxicity in mice. To simulate the clinical application in human beings, nilotinib (25 and 50 mg/kg) was administered to mice 2 hr after APAP intoxication (500 mg/kg). The results indicated that nilotinib (25 mg/kg) (i) abolished APAP-induced liver injury and necro-inflammation, (ii) increased hepatic-reduced glutathione (GSH) and its related enzymes synthesis, (iii) suppressed hepatic oxidative/nitrosative stress cascades, (iv) decreased neutrophil accumulation in the liver, and (v) prevented the over-expression of B-cell lymphoma-2 (bcl-2), cyclin-D1 and stem cell factor receptor (c-Kit) proteins in the liver. Although nilotinib (50 mg/kg) acted through the same mechanisms, there was severe depletion in hepatic GSH content by nilotinib itself at that dose level, rather than the potent stimulation observed by using a dose of 25 mg/kg. Consequently, the mortality rate after 18 hr was 100% for nilotinib (50 mg/kg) + APAP (750 mg/kg) versus 60% for APAP (750 mg/kg) and 40% for nilotinib (25 mg/kg) + APAP (750 mg/kg) in the survival analysis experiment. In conclusion, nilotinib can counteract the hepatotoxicity produced by a non-lethal dose of APAP. However, there is a risk of aggravating the mortality for a lethal dose of APAP when nilotinib is co-administered at doses relatively high, or near to the clinical range because of hepatic GSH depletion and c-kit inhibition.
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PMID:Nilotinib interferes with the signalling pathways implicated in acetaminophen hepatotoxicity. 2411 97


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