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

The c-Myc oncogenic transcription factor (Myc) is pathologically activated in many human malignancies. Myc is known to directly upregulate a pro-tumorigenic group of microRNAs (miRNAs) known as the miR-17-92 cluster. Through the analysis of human and mouse models of B cell lymphoma, we show here that Myc regulates a much broader set of miRNAs than previously anticipated. Unexpectedly, the predominant consequence of activation of Myc is widespread repression of miRNA expression. Chromatin immunoprecipitation reveals that much of this repression is likely to be a direct result of Myc binding to miRNA promoters. We further show that enforced expression of repressed miRNAs diminishes the tumorigenic potential of lymphoma cells. These results demonstrate that extensive reprogramming of the miRNA transcriptome by Myc contributes to tumorigenesis.
 ...
PMID:Widespread microRNA repression by Myc contributes to tumorigenesis. 1806 65

Hematopoietic stem cells (HSCs) are multipotent progenitors that give rise to all types of blood cells. In the present study, we document that HSC development and functions are negatively regulated by the E3 ubiquitin ligase c-Cbl (casitas B-cell lymphoma). HSCs of c-Cbl(-/-) mice exhibit augmented pool size, hyperproliferation, greater competence, and enhanced long-term repopulating capacity. Our mechanistic studies identified that c-Cbl(-/-) HSCs are hyperresponsive to thrombopoietin (TPO) and display elevated levels of STAT5 phosphorylation, thus leading to increased c-Myc expression. In essence, our data unequivocally identify c-Cbl as a novel negative regulator of developmental and functional properties of HSCs.
 ...
PMID:The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells. 1841 9

Pim kinases are found to be highly expressed in leukemia, lymphoma, prostate and pancreatic cancer. Bitransgenic mice overexpressing either Pim-1 or Pim-2 and c-Myc succumb to pre-B-cell lymphoma at a strikingly accelerated speed. Despite that Pim-1/Pim-2 has long been recognized as a strong synergistic partner with c-Myc in tumorigenesis, the mechanism underlying the synergism is still not well understood. Overexpression of Pim-1/Pim-2 kinase dramatically stabilizes c-Myc in vivo, and the stabilization is partially mediated by phosphorylation of c-Myc by Pim kinase on a novel site, Ser329. We provide evidence that Pim-2 is more efficient in directly phosphorylating c-Myc Ser329 to stabilize c-Myc. In contrast, we find that Pim-1 is more effective in mediating a decrease in c-Myc Thr58 phosphorylation and an increase in c-Myc Ser62 phosphorylation than in phosphorylating Ser329. In either case, through stabilizing c-Myc, Pim-1/Pim-2 kinases enhance the transcriptional activity of c-Myc. Also knocking down either Pim-1 or Pim-2 dramatically decreases the endogenous levels of c-Myc and thus, its transcriptional activity. Finally, coexpression of the Pim kinases and c-Myc enhances the transforming activity of c-Myc as does the phosphomimic mutant of c-Myc on Ser329. We conclude that these findings appear to explain at least in part the mechanism underlying the synergism between the Pim kinases and c-Myc in tumorigenesis.
 ...
PMID:Pim kinase-dependent inhibition of c-Myc degradation. 1843 30

A 30-year-old, HIV-positive man with a previous history of an atypical nasopharyngeal Burkitt lymphoma developed fluorodeoxyglucose (FDG) avidity on a routine FDG-positron emission tomography (PET)/computed tomography scan performed 10 months after the completion of all treatment. This new FDG-avid disease was in the area of his initial disease. Flow cytometric assessment of a fine needle aspiration showed a CD10-expressing B-cell population with kappa predominance. The corresponding cytology smears had large atypical lymphoid cells along with smaller lymphocytes and macrophages. Because of the patient's previous history of a CD10(+), high-grade B-cell lymphoma, the cytologic and flow cytometric findings were considered highly suspicious for a B-cell lymphoma. Because the differential diagnosis included a relapsed Burkitt lymphoma versus a second, unrelated lymphoma (the former with a dismal prognosis) it was deemed prudent to obtain more tissue via an open biopsy for confirmation of diagnosis and exact subclassification. An open biopsy, however, revealed a reactive lymph node with enlarged geographic follicles; no lymphoma was demonstrable and c-Myc studies were negative. The patient remains without evidence of disease. Retrospectively, the original flow cytometric assessment was believed to likely represent sampling of hyperplastic germinal centers with significantly expanded CD10(+) B cells. The FDG uptake and the kappa predominance further confounded the interpretation. This case illustrates the pitfalls of standard diagnostic techniques, including PET scanning, cytology, and flow cytometry, particularly in the setting of HIV. It further underscores the importance of adequate clinical correlation and a low threshold for performing open biopsies in such patients.
 ...
PMID:Pitfalls of diagnosis based on abnormal flow cytometry and [(18)F]fluorodeoxyglucose positron emission tomography. 1850 Nov 6

Diagnosis and classification of aggressive mature B-cell lymphoma with atypical morphology remains a challenge. To identify factors that may contribute to the atypical morphology, we selected eight such cases and evaluated their morphologic, immunophenotypic and cytogenetic features and clinical outcomes. The neoplastic cells showed a diffuse monotonous infiltrating pattern with a spectrum of morphology including: 1) L1 lymphoblastic; 2) centroblastic; 3) immunoblastic; and 4) mixed centroblastic and immunoblastic. The lymphoma cells in most cases were positive for CD10 and/or BCL6, and showed BCL2 expression. 6 of 8 cases showed C-MYC rearrangements, and interestingly, all 6 cases demonstrated a proliferation index of < or =90%. 3 of the 6 cases also demonstrated t(14;18). Clinical follow-up indicated that aggressive mature B-cell lymphoma may benefit from more intensified chemotherapeutic regimens used for BL. Our study suggests that aggressive mature B-cell lymphoma with atypical morphology may be another "grey zone lymphoma" lying in the spectrum between Burkitt lymphoma and diffuse large B-cell lymphoma.
 ...
PMID:C-MYC rearrangements are frequent in aggressive mature B-Cell lymphoma with atypical morphology. 1878 24

Aberrant overexpression of the miR-17-92 polycistron is strongly associated with B-cell lymphomagenesis. Recent studies have shown that miR-17-92 down-regulates the proapoptotic protein Bim, leading to overexpression of Bcl2, which likely plays a key role in lymphomagenesis. However, the fact that Jeko-1 cells derived from mantle cell lymphoma exhibit both homozygous deletion of BIM and overexpression of miR-17-92 suggests other targets are also involved in B-cell lymphomagenesis. To identify essential target(s) of miR-17-92 in lymphomagenesis, we first transfected miR-17-92 into 2 genetically distinct B-cell lymphoma cell lines: Raji, which overexpress c-Myc, and SUDHL4, which overexpress Bcl2. Raji transfected with miR-17-19b-1 exhibited down-regulated expression of Bim and a slight up-regulation in Bcl2 expression. On the other hand, SUDHL4 transfectants showed aggressive cell growth reflecting facilitated cell cycle progression at the G(1) to S transition and decreased expression of CDKN1A mRNA and p21 protein (CDKN1A/p21) that was independent of p53 expression. Conversely, transfection of antisense oligonucleotides against miR-17 and miR-20a into Jeko-1 led to up-regulation of CDKN1A/p21, resulting in decreased cell growth with G(1) to S arrest. Thus, CDKN1A/p21 appears to be an essential target of miR-17-92 during B-cell lymphomagenesis, which suggests the miR-17-92 polycistron has distinct targets in different B-cell lymphoma subtypes.
 ...
PMID:MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes. 1894 Nov 11

We established a novel mature B-cell line from a CD5 and CD10 double-positive diffuse large B-cell lymphoma patient, designated as WILL1. WILL1 cells were positive for CD5, CD10, CD19, and CD20. Spectral karyotype (SKY) analysis revealed chromosome 8 signals on 6q27 as well as 14q32. Fluorescence in situ hybridization (FISH) analysis suggested that a translocation break occurred outside the immunoglobulin heavy chain (IGH) gene on 14q32. Moreover, fusion signals of IGH and C-MYC probes were detected on the derivative 6 and derivative 14 chromosomes. Southern blot analysis using a C-MYC exon II fragment failed to detect rearrangement, suggesting that the 8q24 breakpoints lay far up- or downstream of the C-MYC gene. WILL1 is a useful tool to analyze the pathogenesis of CD5 and CD10 double-positive diffuse large B-cell lymphoma, and for molecular cloning of the unique translocation breakpoints of 14q32 and 8q24 and a novel gene on 6q27.
 ...
PMID:Establishment of CD5 and CD10 double-positive mature B-cell line, WILL1, showing complex 8q24 translocation involving 14q32 and 6q27. 1897 86

microRNAs constitute one of the most important discovery in the past few years in the field of gene expression regulation. They can precisely regulate the expression of a specific protein by inhibiting its translation and/or promoting the degradation of its mRNA. In several cancers, the expression of some microRNAs is misregulated, pointing toward the existence of microRNAs with oncogenic or tumour suppressor properties. The miR-17-92 miRNA cluster has been reported to have a pro-oncogenic role in a mouse model system of Myc-induced B cell lymphoma. Some of its targets mRNAs code for proteins with pro-apoptotic or anti-proliferative functions, which shed some light on the mechanism of action of this cluster. On the other hand, a tumour suppressor miRNA like let-7 targets mRNAs coding for oncogenes and is frequently down-regulated in cancers. The finding that c-Myc controls the expression of several of these microRNAs reveals new information on how misregulation of this proto-oncogene can promote tumorigenesis.
 ...
PMID:[Oncogenic and tumour suppressor microRNAs]. 1911 13

Post-transplant lymphoproliferative disorders (PTLDs) occur in 3.5-9% of patients after pediatric cardiac transplantation. Caution is needed when treating patients with PTLD because of the risk of allograft rejection frequently caused by withdrawal of immunosuppression. In this report, we describe a 47-month-old boy who developed PTLD as an ileocecal mass 29 months after cardiac transplantation. Immunosuppressive therapy with cyclosporine A (CyA) had been reduced due to an elevation of Epstein-Barr virus (EBV) titer for 8 months before development of PTLD. Histology of the tumor was diffuse large B cell lymphoma. EBV was detected by in situ hybridization assay. Cytogenetic analysis revealed t(8;14)(q24;q32) and Southern blot analysis detected a c-Myc rearrangement. He was treated with rituximab and combination chemotherapy with excellent response. CyA dose was maintained at reduced levels during chemotherapy and later minimized with introduction of everolimus. The child is free of both PTLD and allograft rejection 41 months after the diagnosis of PTLD.
 ...
PMID:Pediatric post-transplant diffuse large B cell lymphoma after cardiac transplantation. 1915

The MYC family of cellular oncogenes includes c-Myc, N-myc, and L-myc, which encode transcriptional regulators involved in the control of cell proliferation and death. Accordingly, these genes become aberrantly activated and expressed in specific types of cancers. For example, c-Myc translocations occur frequently in human B lymphoid tumors, while N-myc gene amplification is frequent in human neuroblastomas. The observed association between aberrations in particular MYC family genes and specific subsets of malignancies might reflect, at least in part, tissue-specific differences in expression or function of a given MYC gene. Since c-Myc and N-myc share substantial functional redundancy, another factor that could influence tumor-specific gene activation would be mechanisms that target aberrations (e.g., translocations) in a given MYC gene in a particular tumor progenitor cell type. We have previously shown that mice deficient for the DNA Ligase4 (Lig4) nonhomologous DNA end-joining factor and the p53 tumor suppressor routinely develop progenitor (pro)-B cell lymphomas that harbor translocations leading to c-Myc amplification. Here, we report that a modified allele in which the c-Myc coding sequence is replaced by N-myc coding sequence (NCR allele) competes well with the wild-type c-Myc allele as a target for oncogenic translocations and amplifications in the Lig4/p53-deficient pro-B cell lymphoma model. Tumor onset, type, and cytological aberrations are similar in tumors harboring either the wild-type c-Myc gene or the NCR allele. Our results support the notion that particular features of the c-Myc locus select it as a preferential translocation/amplification target, compared to the endogenous N-myc locus, in Lig4/p53-deficient pro-B cell lymphomas.
 ...
PMID:Chromosomal location targets different MYC family gene members for oncogenic translocations. 1917 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>