Ena-DATASET-BCCA-11-01-2017-18:39:57:520-3 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001003140 | EGA |
REPOSITORIES: EGA
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Project description:We analyzed the spectrum and clinical significance of MYC and BCL2 mutations in 347 DLBCL cases from population-based cohort of BC, Canada. Mutational status of MYC and BCL2 coding exons were sequenced using TSCA assay.
| EGAS00001002206 | EGA
Project description:Aggressive double and triple hit (DH/TH) DLBCL feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls post-transcriptional dynamics of key mRNA species including those encoding BCL6, MYC and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E (eukaryotic translation initiation factor 4E). EIF4E drives nuclear export and translation of BCL6, MYC and BCL2 mRNA. eIF4E RIP-sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes BCR signaling, cellular metabolism and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counter-regulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative anti-lymphoma activity in DH/TH DLBCL in vitro and in vivo. We found that eIF4E activity regulates the nuclear export of BCL6, MYC, and BCL2 in DH/TH DLBCLs. To determine the extent of nuclear eIF4E activity in DH/TH DLBCLs and how these programs can support the oncogenic activity of BCL6, MYC and/or BCL2 transcripts, we conducted eIF4E-RIP of nuclear RNA followed by RNA-sequencing in OCI-Ly1 cells in triplicates. To understand the changes in gene expression after ribavarin in a clinically relevant sample, we generated a patient-derived xenograft (PDX) in NSG mice from a de-identified specimen isolated from a patient prior to treatment harboring a triple-hit ABC-type DLBCL. PDX cells from passage four (PDX-4) were implanted into NSG mice. When tumors were palpable, mice were randomized to receive vehicle or 80 mg/kg/b.i.d. ribavarin intraperitoneally for 10 days. We isolated RNA from tumors treated with vehicle (n=2) or ribavarin (n=2) and performed mRNA-seq.
2016-01-11 | E-GEOD-63265 | biostudies-arrayexpress
Project description:Overall, the genetic profile of aggressive B-cell NHL in CAYA in the spectrum of BL and DLBCL is heterogeneous. MYC-R cases mostly displayed a molecular profile close to BL regardless of their morphology, whereas MYC-non-R had a more heterogeneous genetic landscape resembling DLBCL.
2024-10-15 | GSE252948 | GEO
Project description:Overall, the genetic profile of aggressive B-cell NHL in CAYA in the spectrum of BL and DLBCL is heterogeneous. MYC-R cases mostly displayed a molecular profile close to BL regardless of their morphology, whereas MYC-non-R had a more heterogeneous genetic landscape resembling DLBCL.
2024-10-15 | GSE252947 | GEO
Project description:A retrospective analysis of whole transcriptome data for 928 DLBCL patients from REMoDLB clinical trial, identifies a subgroup of molecular high grade (MHG) class that present centroblast-like gene expression, enriched for MYC rearrangement, double-hit (MYC rearrangement accompanied with BCL2 and/or BCL6 rearrangement) and associated with adverse clinical outcome.
2019-01-15 | GSE117556 | GEO
Project description:Aggressive double and triple hit (DH/TH) DLBCL feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls post-transcriptional dynamics of key mRNA species including those encoding BCL6, MYC and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E (eukaryotic translation initiation factor 4E). EIF4E drives nuclear export and translation of BCL6, MYC and BCL2 mRNA. eIF4E RIP-sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes BCR signaling, cellular metabolism and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counter-regulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative anti-lymphoma activity in DH/TH DLBCL in vitro and in vivo.
2016-01-11 | GSE63265 | GEO
Project description:SOX9 was identified as a prognostic biomarker particularly in IGH-BCL2 translocated germinal center B cell (GCB) subtypes of the diffuse large B cell lymphoma (DLBCL) and plays a vital role in lymphomagenesis. However, the molecular mechanism that modulating the aberrant expression of SOX9 in this DLBCL subset remains unknown. We have demonstrated that SOX9 enhanced IGH-BCL2 positive DLBCL subset resistance to either chemotherapy or BCL2 inhibitor. Moreover, we found that inhibition of BCL2 downregulates SOX9 in IGH-BCL2 positive DLBCL subset. We further identified that IRF4 is a key regulator to mediate BCL2 induced SOX9 expression, alongside with the chip-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promote IRF4 entry into the nucleus by enhancing its protein stability, via downregulating of proteosome ubiquitination process, and, therefore, enforce SOX9-mediated phenotypes. Finally, we showed in DLBCL cell lines and xenografted mice model that in vivo inhibition of IRF4 with hIRF4 antisense oligonucleotide (ASO) repressed lymphomagenesis and DLBCL chemoresistance. Altogether, our data support the conclusion that IRF4 plays an essential role in BCL2 induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapse and refractory DLBCL in the future.
2024-09-30 | GSE278092 | GEO
Project description:Activation of the MYC oncogene is common in B-cell lymphomas, and frequently associated with compensatory events that dampen Myc-induced apoptosis, such as over-expression of anti-apoptotic Bcl2-family proteins. For example, concurrent translocations of MYC and BCL2 in a subset of Diffuse large B-cell lymphoma (DLBCL) lead to the high-grade “double-hit” lymphoma subtype (DHL), characterized by dismal prognosis in the face of current front-line regimens, thus calling for the pursuit of tailored therapeutic strategies. Here, we show that Myc and Bcl2 modulate the sensitivity of B-cells to IACS-010759, a selective inhibitor of mitochondrial respiratory complex I. Myc activation in non-transformed lymphoid precursors suppressed endogenous Bcl2 and sensitized the cells to IACS-010759-induced apoptosis. Treatment with the Bcl2 inhibitor venetoclax also sensitized to IACS-010759, while overexpression of Bcl-2 was protective. IACS-010759 engaged an ATF4-driven Integrated Stress Response (ISR) with dual anti- and pro-apoptotic effects, the latter mediated by the CHOP transcription factor, which contributed to selective killing of Myc-overexpressing cells. In line with the above data, IACS-010759 and venetoclax synergized in killing human DHL cells, and showed strong combinatorial effects in a pre-clinical setting. In a Bcl2-negative Burkitt’s lymphoma cell line, instead, IACS-010759 synergized with the Mcl-1 inhibitor S63845. Altogether, our data point to the combination of IACS-010759 with distinct Bcl2-family inhibitors for therapeutic reactivation of the intrinsic apoptotic pathway in Myc-associated B-cell lymphomas
2022-03-01 | GSE149073 | GEO
Project description:Intratumor heterogeneity (ITH) in oncogene expression is common in cancer, but it is not known if oncogenes exert combinatorial effects at the single cell level to influence clinical outcome. We address this question using quantitative spectral imaging to simultaneously measure the cellular co-expression of the oncogenes MYC, BCL2 and BCL6 in clinically annotated cohorts of Diffuse Large B-Cell Lymphoma (DLBCL). Unlike in non-malignant lymphoid tissue, where the co-expression of these oncogenes is spatially constrained, DLBCL samples show multiple permutations of oncogenic co-expression at the single cell level. Oncogene co-expression follows clustered and non-random spatial distribution, and is typically stable across different regions of a tumour. Interestingly, we noted that the extent of cells with the unique oncogene combination MYC+BCL2+BCL6- (M+2+6-) associates consistently with patient survival across three independent DLBCL cohorts. We then show that the fraction of M+2+6- co-expressing cells can be inferred from quantitative single oncogene data, as the overall frequencies of co-expression of these oncogenes are stochastic. Predicted values of M+2+6- cellular co-expression frequency from immunohistochemistry of MYC/BCL2/BCL6 (n=316) and multiple independent gene expression datasets (n=2522; 8 cohorts) consistently correlate with survival after R-CHOP chemotherapy, offering a novel strategy for identification of high-risk DLBCL. Finally, we use comparative RNAseq analysis of patient-derived M+2+6+ and M+2+6- B-cells to identify cyclin D2 as a potential BCL6-repressed mediator of the aggressive behavior of M+2+6- population. Overall, our work demonstrates that patterns of oncogene co-expression analyzed at single-cell resolution are clinically relevant, with implications for both diagnostics and target discovery in other cancer types.
2022-05-23 | GSE203446 | GEO
Project description:The pathogenesis of c-MYC and BCL2 double-expressor diffuse large B cell lymphoma (DE DLBCL) remains unclear, particularly in terms of the tumor microenvironment. We aimed to analyze the immune microenvironment of DE DLBCLs to understand the basis of DE-DLBCL's aggressiveness and identify potential therapeutic targets. To discover the key features of DE-DLBCL, fourteen non-DE and 14 DE DLBCL samples underwent RNA-seq analysis. For validation, formalin-fixed paraffin-embedded tissues from 126 patients were immunostained for CD3, CD4, CD8, FOXP3, CD68 and CD163. Two c-MYClow/BCL2low DLBCL (SU-DHL-10 and HT) and 2 c-MYChigh/BCL2high DLBCL cell lines (DOHH2 and OCI-LY8) were used for in vitro assays. The prognostic impact of differential chemokine secretion and immune profiles was evaluated in a mouse tumor model. RNA-seq analysis revealed significantly higher CCL2 and CCR2 mRNA in DE DLBCLs (Padj < 0.05). Public datasets showed higher M2/macrophage ratio and lower T cell infiltration in DE DLBCLs (P < 0.05). Immunohistochemistry confirmed higher M2 macrophages and M2/total macrophage ratio in DE DLBCL (P=0.010 and P=0.098, respectively). In vitro, c-MYChigh/BCL2high cell lines exhibited increased CCL2 secretion, as seen in RNA-seq analysis. Knockdown and overexpression studies identified that MYC and BCL2 overexpression increased CCL2 secretion by upregulation of NF-κB p65 subunit, and the increased CCL2 secretion was crucial for M2 polarization. In mouse tumor models, CCL2 was related to aggressive tumor growth and an immunosuppressive tumor microenvironment. In conclusion, the increased CCL2/CCR2 axis confers aggressiveness of DE DLBCLs by increasing M2 polarization.
2024-09-30 | GSE252690 | GEO