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)

Cross-linking of surface Ig receptors with anti IgM (anti-mu heavy chain, anti-mu), but not anti-IgD (anti-delta heavy chain, anti-delta), Abs leads to growth arrest and apoptosis in several extensively characterized B cell lymphomas. By poorly understood mechanisms, both Igs transiently stimulate c-Myc protein expression. However, ultimately, only anti-mu causes a severe loss in c-Myc and a large induction of p27(Kip1) protein expression. Because phosphatidylinositol 3-kinase (PI3K) has been established as a major modulator of cellular growth and survival, we investigated its role in mediating anti-Ig-stimulated outcomes. Herein, we show that PI3K pathways regulate cell cycle progression and apoptosis in the ECH408 B cell lymphoma. Anti-mu and anti-delta driven c-Myc protein changes precisely follow their effects on the PI3K effector, p70(S6K). Upstream of p70(S6K), signaling through both Ig receptors depresses PI3K pathway phospholipids below control with time, which is followed by p27(Kip1) induction. Conversely, anti-delta, but not anti-mu stimulated PI3K-dependent phospholipid return to control levels by 4-8 h. Abrogation of the PI3K pathway with specific inhibitors mimics anti-mu action, potentiates anti-mu-induced cell death and, importantly, converts anti-delta to a death signal. Transfection with active PI3K kinase construct induces anti-mu resistance, whereas transfection with dominant negative PI3K augments anti-mu sensitivity. Our results show that prolonged disengagement of PI3K or down-regulation of its products by anti-mu (and not anti-delta) determines B cell fate.
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PMID:Role of phosphatidylinositol 3-kinase in anti-IgM- and anti-IgD-induced apoptosis in B cell lymphomas. 1116 Feb 3

Despite advances in treatment, long-term outcome of patients with diffuse large B cell lymphoma (DLBCL) is no better today than reported in 1975. A recent study applying DNA microarray technology revealed that patients whose cancer related to patterns of genes expressed in germinal center lymphocytes responded more favorably to chemotherapy than patients whose cancer related to patterns of genes expressed in activated lymphocytes. cDNA and oligonucleotide microarrays are described, and their applications in cancer research are reviewed. In addition to DLBCL, microarray technology has been used to study several types of cancer. The applications of microarray technology are numerous and include profiling gene expression patterns in order to facilitate diagnosis and predict response to therapy; correlating patterns of gene expression with prognosis; and identifying genes and gene products that are associated with tumorigenic phenotype or with drug resistance, among other applications. Microarraytechnology has also been used in cell lines to correlate gene expression and chemotherapy response. Furthermore, microarray technology may provide a useful tool to examine the development of drug resistance in cancer and has recently been used to study changes in gene expression caused by activated c-Myc in primary human fibroblasts. Tissue microarrays are described. In addition to the amplification of limited tissue re sources, tissue microarrays have the advantages of limiting the variability associated with tissue processing and limiting the necessary amount of reagent. Tissue microarrays have been used to determine the frequencies of amplication of 3 major breast cancer genes and identify overexpression of ERBB2 mRNA; assess and compare gene amplification in benign prostatic hyperplasia, primary prostate carcinoma, recurrent prostate tumors, and metastatic tumors; compare aggressiveness of prostate carcinoma in 2 patient populations; and study gene amplification across various tumor types. Furthermore, DNA microarray and tissue microarray techniques can be combined to provide convergent evidence of findings and to examine different aspects of gene expression. DNA array technology may also be used to identify critical molecular targets or to identify the critical rate-limiting step in a cascade of genes under the influence of a mutated gene. The historical progression of goals of the National Cancer Institute is reviewed, as well as the economic impact of reduction in cancer-associated mortality. Future efforts should continue the investment in basic research and more effectively integrate it with clinical trials and with approaches to prevention and treatment.
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PMID:National Oncology Forum: perspectives for the year 2000. 1150 81

The Fifteenth International Symposium of the Foundation for Promotion of Cancer Research entitled 'New Horizons in the Diagnosis and Treatment of Hematological Malignancies Based on Molecular Genetic Features' was held in Tokyo on January 15-17, 2002. Twenty-nine invited speakers, including 12 from abroad and 17 from Japan, presented the updated results of their research. After an overview of the classification of hematological malignancies, new findings on some disease entities based on novel immunophenotypic and molecular genetic features were presented. The results of gene expression profiling and BCL6 and C-MYC gene rearrangement in diffuse large B-cell lymphoma were presented and oncogenic mechanism of acute myeloid leukemia was discussed. In the treatment of non-Hodgkin's lymphoma and acute leukemia, the present consensus and future directions were discussed based on the results of multicenter trials in the USA and Japan. As a molecular targeting therapy, the remarkable effect of a BCR-ABL tyrosine kinase inhibitor, STI571, in chronic myeloid leukemia and gastrointestinal stromal tumor was presented. Thereafter, promising results of active immunotherapy, chimeric anti-CD20 monoclonal antibody, anti-CD20 radioimmunoconjugate and anti-CD22 immunotoxin for B-cell lymphoma were presented. Finally, recent advances in allogeneic hematopoietic stem cell transplantation were discussed, focusing on reduced-intensity preparative regimens. The recent advances in basic and clinical research on hematological malignancies would lead to further improvement in the prognosis and quality of life of patients suffering from leukemia or lymphoma.
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PMID:Report of the fifteenth international symposium of the foundation for promotion of cancer research: new horizons in the diagnosis and treatment of hematological malignancies based on molecular genetic features. 1241 6

In the European Organization for Research and Treatment of Cancer (EORTC) classification 2 types of primary cutaneous large B-cell lymphoma (PCLBCL) are distinguished: primary cutaneous follicle center cell lymphomas (PCFCCL) and PCLBCL of the leg (PCLBCL-leg). Distinction between both groups is considered important because of differences in prognosis (5-year survival > 95% and 52%, respectively) and the first choice of treatment (radiotherapy or systemic chemotherapy, respectively), but is not generally accepted. To establish a molecular basis for this subdivision in the EORTC classification, we investigated the gene expression profiles of 21 PCLBCLs by oligonucleotide microarray analysis. Hierarchical clustering based on a B-cell signature (7450 genes) classified PCLBCL into 2 distinct subgroups consisting of, respectively, 8 PCFCCLs and 13 PCLBCLsleg. PCLBCLs-leg showed increased expression of genes associated with cell proliferation; the proto-oncogenes Pim-1, Pim-2, and c-Myc; and the transcription factors Mum1/IRF4 and Oct-2. In the group of PCFCCL high expression of SPINK2 was observed. Further analysis suggested that PCFCCLs and PCLBCLs-leg have expression profiles similar to that of germinal center B-cell-like and activated B-cell-like diffuse large B-cell lymphoma, respectively. The results of this study suggest that different pathogenetic mechanisms are involved in the development of PCFCCLs and PCLBCLs-leg and provide molecular support for the subdivision used in the EORTC classification.
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PMID:Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. 1530 63

The present study aimed to characterize the clinical and molecular-cytogenetic features of non-Hodgkin's lymphoma (NHL) with double translocation of the immunoglobulin heavy chain (IGH) gene. G-banding analysis, fluorescence in situ hybridization (FISH) with the IGH (Cgamma and VH) and oncogene (c-MYC, BCL1, BCL2, and BCL6) probes, and long-distance polymerase chain reaction (LD-PCR) were performed on 6 patients with B-cell lymphoma, one with angioimmunoblastic T-cell lymphoma, and one with acute lymphoblastic leukemia (ALL) with B-cell phenotype. G-banding analysis detected two different 14q32 translocations, t(14,18) and add (14)(q32) in a patient with ALL. Two distinct partners of double IGH translocation identified by FISH were as follows: c-MYC + BCL2 in 3 patients, c-MYC + BCL1 in 2, c-MYC + BCL6 in one, BCL2 + 9q22 in one, and 1q21 + 6q27 in one. Colocalization of BCL1 and c-MYC probes was demonstrated in a patient with mantle cell lymphoma. LD-PCR detected c-MYC/Cmu, c-MYC/Calpha and BCL6/Cmu, and c-MYC/Calpha fusion in each one patient. Seven of 8 patients showed high serum LDH. Central nervous system and leukemic involvement was observed in 5 and 6 patients, respectively. Median survival time of patients with c-MYC/IGH translocation was 9 months. The results defined a clinical subset of B-cell lymphoma/leukemia showing extremely poor prognosis. C-MYC/IGH translocation is possibly an evolutionary alteration following the primary IGH translocation with BCL1, BCL2, or BCL6. Furthermore, FISH identified one novel (9q22) and one cryptic chromosomal breakpoints (6q27) involved in IGH translocation.
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PMID:Molecular-cytogenetic characterization of non-Hodgkin's lymphoma with double and cryptic translocations of the immunoglobulin heavy chain gene. 1537 Feb 7

The c-Myc transcription factor regulates a wide set of genes involved in processes such as proliferation, differentiation and apoptosis. Therefore, altered expression of Myc leads to deregulation of a large number of target genes and, as a consequence, to tumorigenesis. For understanding Myc-induced transformation, identification of these target genes is essential. In this study, we searched for Myc target genes involved in lymphomagenesis using different mouse T and B cell lymphoma cell lines transformed by a conditional Myc-allele. Target genes obtained by microarray experiments were further subjected to a kinetic analysis of mRNA expression upon Myc inactivation/reactivation, bioinformatic examination of Myc binding sites and chromatin immunoprecipitation. This approach allowed us to define targets whose activation is a direct consequence of Myc binding. Among the 38 novel Myc targets, we identified several genes implicated in the tumor development. These genes are not only relevant for mouse lymphomas because we observed their upregulation in human lymphomas as well. Our findings further the understanding of Myc-induced lymphomagenesis and help toward developing more efficient antitumor strategies.
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PMID:Identification of novel Myc target genes with a potential role in lymphomagenesis. 1547 87

Translocations involving chromosome 8 are the most common aberrations in B-cell non-Hodgkin lymphoma (B-NHL). The presence of the typical t(8;14)(q24;q32) or its variants has been confirmed in all cases of Burkitt lymphoma (BL), in some cases of Burkitt-like lymphoma (BLL), and in diffuse large B-cell lymphoma (DLBCL). The alterations lead to deregulated expression of c-myc protein by a chromosomal translocation joining C-MYC gene with sequences from immunoglobulin (Ig) enhancers. The C-MYC gene rearrangement plays an essential role in leukemogenesis of BL and probably plays a part in other aggressive NHLs. The present study was undertaken to compare the cytogenetic features in cases of BL, BLL, and DLBCL. We detected chromosomal aberrations by G-banding and fluorescence in situ hybridization (FISH) painting in 10 cases of aggressive B-NHL and used FISH to visualize the C-MYC gene rearrangement. Chromosome 8 was most frequently involved in structural aberrations (8/10 cases), and 4 cases showed the typical t(8;14)(q24;q32). Only two of 5 patients suspected of having BL fulfilled all the criteria for this diagnosis; in the others, chromosome 8 was aberrant, but the absence of C-MYC rearrangement or the results of flow cytometry excluded the diagnosis of BL. All BLL cases showed C-MYC overexpression, but only one had a rearrangement of the C-MYC gene; the remaining cases showed other aberrations of chromosome 8. This study indicates that the mechanisms of C-MYC activation involved in BLL can be different from that for the BL.
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PMID:Frequent aberrations of chromosome 8 in aggressive B-cell non-Hodgkin lymphoma. 1564 90

The BCL-2 family has been implicated in the pathogenesis of various hematopoietic malignancies, including follicular non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia. To identify genes that act synergistically in BCL2-enforced leukemogenesis, we developed a murine B-cell lymphoma/leukemia model based on the IL-3-dependent Balb/C pro-B line (FL5.12). FL5.12 cells were stably transfected with antiapoptotic BCL-2 alone or in combination with proapoptotic BAX or nonfunctional mutant BAX, thereby creating various levels of imbalance within the BCL-2 family. Transfectants were intravenously injected into normal Balb/C mice. Whereas FL5.12 cells did not provoke leukemia, mice injected with stable transfectants died of leukemia over time. Disease incidence and latency time depended on the degree of imbalance in the BCL-2 family, supporting a model whereby BCL2 drives tumorigenesis. All mice presented with hepatosplenomegaly and leukemic FL5.12 cells in peripheral blood and bone marrow compartments. Leukemic conversion was accompanied by secondary genetic aberrations leading to clonal IL-3-responsive leukemia. Cellular transformation was independent of alterations in c-Myc or downstream apoptotic pathway. Leukemic clones retained a normal DNA damage response leading to elevated P53 and P21 levels and cell cycle arrest upon irradiation. In conclusion, our mouse model may prove a valuable tool to identify genes that cooperate in BCL2-enforced lymphoma/leukemogenesis.
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PMID:Novel murine B-cell lymphoma/leukemia model to study BCL2-driven oncogenesis. 1564 25

We used gene targeting in mice to insert a His(6)-tagged mouse c-Myc cDNA, Myc(His), head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5' of the intronic enhancer, Emu. The insertion of Myc(His) mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, Myc(His) transgenic mice developed B-cell and plasma neoplasms, such as IgM(+) lymphoblastic B-cell lymphomas, Bcl-6(+) diffuse large B-cell lymphomas, and CD138(+) plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc(His), and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of Myc(His), suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19(Arf)-Mdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc(His) insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Myc-activating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation.
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PMID:Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice. 1573 16

The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.
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PMID:Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. 1609 55


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