LEF1 in Burkitt lymphoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42637 | GEO | 2013/06/01
SECONDARY ACCESSION(S): PRJNA182484
REPOSITORIES: GEO
Similar Datasets
Project description:Recently global gene expression profiling of patients samples lead to a molecular definition of Burkitt Lymphoma (BL) with lymphocyte enhancer-binding factor 1 (LEF1) as a signature gene. Here we report the discovery of nucleic LEF1 in a very high proportion of BL cases (15/18) and LEF1 target genes. Germinal center B cells were devoid of detectable nuclear LEF1 expression as mantle cell lymphoma (0/5), marginal zone lymphoma (0/6), follicular lymphoma (0/12) or diffuse large B cell lymphoma (DLBCL) (1/31). Using whole genome gene expression profiling after transient knockdown of LEF1 in BL cell lines, new LEF1 target genes were identified. The joint expression of these genes in primary BL samples shows that LEF1 is not only expressed aberrantly in BL but also transcriptionally active. Our study identified aberrantly expressed LEF1 and its target genes suggesting an important functional role in BLs. 3 biological replicates scrb siRNA vs LEF1 si RNA , 4 siRNA are pooled
2013-06-01 | E-GEOD-42637 | biostudies-arrayexpress
Project description:Recently, a subset of MYC-translocation negative aggressive B-cell lymphomas resembling Burkitt lymphoma (BL) characterized by proximal gains and distal losses in the long arm of chromosome 11 has been described. In the 2016 revision of the WHO classification these MYC-translocation negative lymphomas have been introduced as new provisional entity designated “Burkitt-like lymphoma with 11q aberration” (MNBLL 11q). Here, we show a comprehensive flow-cytometry analysis of 10 MNBLL 11q cases, well characterized genetically and pathologically. Twenty-three cases of MYC-positive BL, including three cases carrying both MYC rearrangements and 11q aberration, served as controls. All MNBLL 11q were CD20+/CD10+/BCL6+/BCL2- /MUM1- /MYC+/EBV negative , presented a high proliferation rate and showed a three-year overall survival (80%) similar to BL patients, with no recurrence after the end of treatment. MNBLL 11q immunophenotype was similar to that of MYC-positive BL without and with 11q, except for less frequent CD38higher expression (10% MNBLL 11q vs 91% MYC-positive BL, p<0.001), less frequent diminished CD45 expression (90% vs 23%, p=0.001), and CD16/CD56 co-expression (60% vs 0%, p<0.001). Our findings suggest subtle but important differences in MNBLL 11q immunophenotypes and MYC-positive BLs, which could not only aid in the differential diagnosis but also in the understanding of the pathogenesis of MNBLL 11q.
2019-07-30 | GSE93002 | GEO
Project description:Burkitt lymphoma (BL) is an aggressive, MYC-driven lymphoma comprising three distinct clinical subtypes, including sporadic BLs that occur worldwide, endemic BLs that occur predominantly in sub-Saharan Africa, and immunodeficiency-associated BLs that occur primarily in the setting of HIV. In this study, we comprehensively delineated the genomic basis of BL through whole genome sequencing of 101 tumors representing all 3 subtypes of BL to identify 72 driver genes. These data were additionally informed by CRISPR screens in BL cell lines to functionally annotate the role of oncogenic drivers. Nearly every driver gene was found to have both coding and non-coding mutations highlighting the importance of whole genome sequencing for identifying driver events. Our data implicate coding and non-coding mutations in IGLL5, BACH2, SIN3A and DNMT1. EBV infection was associated with higher mutation load, with EBV type 1 showing a higher mutational burdens than type 2 EBV. While sporadic and immunodeficiency-associated BLs had similar genetic profiles, endemic BLs manifested more frequent mutations in BCL7A and BCL6, and fewer genetic alterations in DNMT1, SNTB2, CTCF. Silencing mutations in ID3 were a common feature of all three subtypes of BL. In vitro, mass spectrometry-based proteomics demonstrated that the ID3 protein binds primarily to TCF3 and TCF4. In vivo knockout of ID3 potentiated the effects of MYC, leading to rapid tumorigenesis and tumor phenotypes consistent with those observed in the human disease.
| EGAS00001003778 | EGA
Project description:BCL6 is a key oncogene in lymphoma pathogenesis. The expression of BCL6 in lymphoid cells can be deregulated by several mechanisms, including chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a major ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in diffuse large B-cell lymphoma (DLBCL). In this work, we found that FBXO11 is frequently mutated in Burkitt lymphoma (BL) but rarely mutated in other BCL6-positive lymphomas, such as follicular lymphoma (FL). All mutations tested impaired FBXO11 mediated BCL6 degradation and FBXO11 knock-out completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of one copy or both copies of FBXO11 in c-Myc-driven B cell lymphoma in mice accelerated lymphomagenesis, genetically confirming that FBXO11 is a haplo-insufficient oncosuppressor in lymphoma. In both FBOX11 WT and deficient BL mouse and human cell lines, blockade of BCL6 via a specific degrader or BCL6 inhibitors, impaired lymphoma growth in vitro and in vivo, an effect further enhanced by co-inhibition of c-Myc activity. Overall these findings not only establish FBXO11 as one of the most frequently mutated genes in BL, but also elucidate its biological functions in lymphomagenesis and thereby identify BCL6 as a specific therapeutic target in BL.
2021-12-31 | GSE159303 | GEO
Project description:To identify genes mediating tumor transformation we compared the transcriptome of five Burkitt lymphoma (BL) cell lines (tumor cells) with that of a pool of three lymphoblastoid B-cell lines (LCL; immortal, but not tumor cells). Each BL cell line was considered as a biological replicate. BL cell lines: DG-75, Ramos, BL2, Mutu-I and Akata. LCL cell lines: X50-7, IB4 and Dana.
2015-09-30 | GSE41865 | GEO
Project description:MicroRNAs (miRNAs) are small non-coding RNAs involved in the posttranscriptional regulation of gene expression. Deregulated miRNA levels have been reported in Burkitt lymphoma (BL) compared to normal B cells and a number of miRNA target genes have been identified in BL cell lines. Here, we determined for the first time the miRNA targetomes of primary BL tumors in comparison with normal B cells. AGO2-RNA immunoprecipitation (AGO2-RIP) in two frozen diagnostic BL tissue samples and three CD19+ B-cell samples isolated from routinely removed tonsils revealed distinct miRNA targetomes of BL and normal B cells. Targets of the miR-17~92 cluster were significantly more frequently AGO2-IP enriched in BL while targets of miR-29 and miR-150 were more frequently AGO2-IP enriched in normal B cells. Furthermore, we showed that miRNA target genes in BL are mainly involved in cell cycle and cell death. Immunohistochemistry on BL tumor samples and tonsil tissues confirmed altered protein levels for two out of six selected miRNA targets, in line with the differential AGO2-IP enrichment between BL and normal B cells. A comparison of AGO2-IP enriched genes in primary BL cases with BL cell lines indicated that approximately half of the miRNA targets may be missed in studies using BL cell lines, while almost 60% of miRNA target genes identified in cell lines were not AGO2-IP enriched in primary BL cases. Our results demonstrate both the necessity and feasibility of studying miRNA-target interactions in primary tumors.
2018-01-19 | GSE107325 | GEO
Project description:In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis.
2012-08-14 | GSE35219 | GEO
Project description:To gain further knowledge on the role of microRNAs (miRNAs) in the pathogenesis of Burkitt lymphoma (BL), we performed small RNA sequencing in BL cell lines and normal germinal center B (GC-B) cells. This revealed 26 miRNAs with significantly different expression levels. Altered levels were validated by qRT-PCR for six of eight selected miRNAs. For five miRNAs, the differential expression pattern was confirmed in BL primary tissues compared to GC-B cells. Inhibition of miR-378a-3p reduced the growth of multiple BL cell lines. RNA immunoprecipitation of Argonaute 2 followed by microarray analysis (Ago2-RIP-Chip) upon inhibition and ectopic overexpression of miR-378a-3p revealed 63 and 20 putative miR-378a-3p targets, respectively. These included 28 genes with a putative miR-378a-3p binding site. Effective targeting by miR-378a-3p was confirmed by luciferase reporter assays for four out of eight selected genes: MNT, FOXP1, IRAK4, and lncRNA JPX, all of which have been implicated in proliferation and cancer. In summary, our study identified several differentially expressed miRNAs in BL. We identified miR-378a-3p as a miRNA with an oncogenic role in BL and revealed 4 novel miR-378a-3p target genes, i.e. MNT, FOXP1, IRAK4, and JPX.
2020-06-30 | GSE141691 | GEO
Project description:Burkitt’s lymphoma (BL) is an aggressive B-cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Because of their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Hence, there is a need for targeted therapies. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We observed that, among other compounds, inhibitors of heat shock protein 90 (HSP90) induce apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling, we found that in BL, HSP90 inhibition compromises activity of the pivotal B cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Hence, our study provides a molecular rationale for the use of HSP90 inhibitors in the treatment of BL by demonstrating that HSP90 inhibition interferes with tonic BCR signaling and thus impairs BL cell survival.
2017-01-02 | PXD004181 | Pride
Project description:In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis. All samples were obtained from murine lymphomas (Cgamma1-cre; R26StopFLMYC;R26StopFLP110* animals). Cells used for microarray analysis were sorted reporter positive cells. Tumour cells were compared to a matched germline DANN sample to identify acquired aberrations.
2012-08-13 | E-GEOD-35219 | biostudies-arrayexpress