Filters
Technology
Platform
GSE23501
Homo sapiens
67 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We performed DNA methylation (HELP array) and gene expression profiling in 69 samples of diffuse large B cell lymphoma (DLBCL). First, by gene expression, two molecular subtypes of DLBCL termed as "germinal center B cell-like" (GCB) and "activated B cell-like" (ABC) DLBCL were assigned to the 69 DLBCL cases. Then, the supervised analysis using HELP data revealed strikingly different DNA promoter methylation patterns in the two molecular DLBCL subtypes. These data provide epigenetic evidence that the DLBCL subtypes are distinct diseases that utilize different oncogenic pathways.
Publication Title
DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
Illumina Genome Analyzer IIx
Description
Maternal 5-HT1A-receptor (R) is required for the timely development of the hippocampus and the establishment of emotional behaviors in Swiss-Webster (SW) mice. A partial and/or complete loss of maternal 5-HT1AR results in delayed ventral dentate granule cell (v-DGC) development and subsequent anxiety-like phenotype in the wild-type offspring by a non-genetic, presumably epigenetic mechanism. Here we tested v-DGCs for genome-wide DNA methylation changes elicited by the receptor deficient maternal environment. We identified a set of hypomethylated regions in the offspring of receptor deficient mothers. A significant fraction of these maternal-differentially methylated regions (m-DMRs) mapped to strong CpG islands, sequences that are typically not methylated or if methylated, resistant to environmental-induced changes. Many m-DMRs mapped to exons and some were associated with expression changes. Their hypomethylation was due to an arrest in de novo methylation and, to a lesser extent, to demethylation during postnatal life indicating that the perturbation in methylation coincides with the developmental delay in DGC maturation in the offspring of receptor deficient mothers. Inhibiting methylation in differentiating neurons impaired their maturation further suggesting a link between de novo methylation and neuronal differentiation. These data suggest that methylation at specific exonic CpG-islands may contribute to the mechanism through which maternal 5-HT1AR modulates hippocampal development and consecutively the level of anxiety in the SW offspring. Reduced 5-HT1AR-binding has been reported in individuals, particularly in association with anxiety/depression, including peri/postpartum depression. Therefore, maternal receptor deficit may contribute, via a non-genetic mechanism, to the high prevalence and heritability of anxiety disorders in human. Overall design: Examined transcriptomes of 5HT1A wild type offspring with 5HT1A wild type/heterozygous mother or 5HT1A KO offspring with 5HT1A of heterozygous/knock out mother
Publication Title
Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 58 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
Deregulation of the translational machinery is emerging as a critical contributor to lymphomagenesis. Various miRNA alterations have been identified in lymphoma, but their role in disrupting the cap-dependent translation regulation complex remains poorly understood. Here, we demonstrate the translation initiation factor, eIF4GII, as a direct target and major mediator of miR-520c-3p function through 3UTR of eIF4GII mRNA. We established that elevated miR-520c-3p represses translation, initiates premature senescence and blocks cell proliferation in diffuse large B-cell lymphoma (DLBCL). Moreover, miR-520c-3p overexpression diminishes DLBCL cells colony formation and reduces tumor growth in a lymphoma xenograft mouse model. miR-520c-3p overexpressing cells display lowered eIF4GII levels. Consequently, downregulation of eIF4GII by siRNA induces cellular senescence, decreases cell proliferation and ability to form colonies. Our in vitro and in vivo findings we further validated in patient samples; DLBCL primary cells demonstrated low miR-520c-3p levels with reciprocally highly up-regulated eIF4GII protein expression. In contrast, normal donor B-cell lymphocytes had low levels of eIF4GII protein and elevated miR-520c-3p levels. Our results provide evidence that the tumor suppressor effect of miR-520c-3p is mediated through repression of cap-dependent translation while inducing senescence and that eIF4GII is a key effector of this anti-tumor activity. These findings may have implications for therapeutic interventions in patients with DLBCL.
Publication Title
Down-regulation of eIF4GII by miR-520c-3p represses diffuse large B cell lymphoma development.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Heat shock protein 90 (Hsp90) is an emerging therapeutic target in cancer. We report that Hsp90 inhibitors selectively kill DLBCLs that are biologically dependent on the BCL6 transcriptional repressor. We examined the pharmacokinetics, toxicity and efficacy of PUH71, a recently developed purine scaffold Hsp90 inhibitor. PUH71 preferentially accumulated in tumors vs. normal tissues, and unlike the widely used benzoquinone Hsp90 inhibitors, displayed no signs of organ toxicity. PUH71 selectively and potently induced the regression of BCL6-dependent DLBCLs in vivo, through reactivation of key BCL6 target genes and apoptosis.
Publication Title
A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
Loss of Tet1 expression causes global 5mC and 5hmC changes in stem and progenitor cells in mice and enhanced pro-B cell self-renewal, increased DNA damage and B-lymphomageneis. In this study we performed whole transciptome analysis using RNA-sequencing in purified long-term HSCs and MPPs. These results revealed that genes regulated byTet1 included Histones, DNA repair enzymes and B-lineage specific factors. Overall design: Purified long-term HSCs and MPPs from WT and Tet1 KO mice were used for RNA isolation. RNA was extracted using RNeasy kit (Qiagen) and PolyA selection using oligo-dT beads (Life Technologies) was performed according to the manufacturer's instructions. Libraries were generated as described before, including end-repair, A-tailing, adapter (Illumina Truseq system) ligation and PCR amplification. RNA libraries were then sequenced on the Illumina HiSeq 2000 using 50bp paired-end reads. Transcriptome profiling of LT-HSC and MPP cells in WT and Tet1 KO mice
Publication Title
TET1 is a tumor suppressor of hematopoietic malignancy.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Using RNA-seq we identified the gene expression changes in GC B cells from LSD1 wild-type or LSD1-deficient mice immunized with T cell dependent antigens (Sheep Red Blood cells) Overall design: RNA seq of sorted GC B cell populations from 3 littermate mice per genotype (3 wild-type, 3 knockout)
Publication Title
Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Mantle Cell Lymphoma (MCL) is a mostly incurable malignancy arising from nave B cells (NBC) in the mantle zone of lymph node follicles. We analyzed genome-wide methylation in MCL patients using the HELP (Hpa II tiny fragment Enrichment by Ligation mediated PCR) assay and found significant aberrancy in promoter methylation patterns as compared to normal NBCs. Using biological and stringent statistical criteria, we further identified four hypermethylated genes CDKN2B, MLF-1, PCDH8, HOXD8 and four hypomethylated genes CD37, HDAC1, NOTCH1 and CDK5 where aberrant methylation was associated with inverse changes in mRNA levels. MassArray Epityper analysis confirmed the presence of differential methylation at the promoter region of these genes. Immunohistochemical analysis of an independent cohort of 14 MCL patient samples, confirmed CD37 surface expression in 93% of patients, validating its selection as a target for MCL therapy. Treatment of MCL cell lines with a novel small modular immunopharmaceutical(CD37-SMIP) resulted in significant loss of viability in cell lines with intense surface CD37 expression. Treatment of MCL cell lines with the DNA methyltransferase inhibitor decitabine resulted in reversal of aberrant hypermethylation and synergized with the HDAC inhibitor SAHA in induction of the four hypermethylated genes CDKN2B, MLF-1, PCDH8 and HOXD8. The combination of Decitabine and SAHA also resulted in potent and synergistic anti-MCL cytotoxicity as compared to either drug alone. In conclusion, our analysis shows prominent and aberrant methylation of the MCL genome and identifies novel differentially methylated and expressed genes in MCL cell lines and patient samples. Furthermore, our data suggest that differentially methylated genes can be targeted for therapeutic benefit in MCL.
Publication Title
Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma.
Sample Metadata Fields
Disease, Cell line
View Samples- Homo sapiens
- 18 Downloadable Samples
- Illumina HiSeq 2000
Description
BCL6 inhibitor induces derepression of BCL6 target genes and shows a similar transcriptional program to BCL6 siRNA Overall design: Genome-wide profiling of mRNA transcript levels in human DLBCL cell line with BCL6 inhibitor and DMSO control.
Publication Title
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 3 Downloadable Samples
- Illumina HiSeq 2000
Description
Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands. Overall design: gene expression profiles of DLBCL cases
Publication Title
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
Resting B cells were isolated from WT or KMTD KO mice by immunomagentic depletion of with anti-CD43 beads. Gene expression use determined by RNAseq in resting B cells or B cells stimulated with LPS, IL4, and anti-mouse CD180 for 3 days. Overall design: RNAseq was used to profile unstimulated resting B cells (n=3) and B cells stimulated for 3 days (n=3).
Publication Title
The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.
Sample Metadata Fields
No sample metadata fields
View Samples