Filters
Technology
Platform
GSE99358
Homo sapiens
3 Downloadable Samples
Affymetrix Human Transcriptome Array 2.0 (hta20), Illumina HiSeq 2000
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Loss of <i>FAM46C</i> Promotes Cell Survival in Myeloma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
Publication Title
Loss of <i>FAM46C</i> Promotes Cell Survival in Myeloma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy.
Publication Title
Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrative transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P <0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL.
Publication Title
An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma.
Sample Metadata Fields
Specimen part, Disease
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrative transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P <0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL.
Publication Title
An integrated genomic and expression analysis of 7q deletion in splenic marginal zone lymphoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 42 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Clonal competition with alternating dominance in multiple myeloma.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 42 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Copy number and expression profiling of multiple myeloma patients at multiple stages of their individual clinical course
Publication Title
Clonal competition with alternating dominance in multiple myeloma.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 38 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
The rat models of colorectal cancer (CRC), such as the azoxymethane (AOM) cancer-inducing model, are important tools for researching cancer initiation pathways. However, there is limited understanding of the expression pathways of underlying normal rat colonic epithelium and how this relates to human colonic epithelium. The aim of this study was to study the acute effects of AOM on the gene and pathway expression of the rat's colonic epithelium, whilst contrasting the background normal global expression patterns along the length of the rat as compared to the normal human colonic epithelium.
Publication Title
Genomic homeostasis is dysregulated in favour of apoptosis in the colonic epithelium of the azoxymethane treated rat.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Waldenstrms macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in the bone marrow and immunoglobulin M paraprotein production. Cytogenetic analysis is limited by the difficulty in obtaining tumor metaphases and the genetic basis of the disease remains poorly defined. We performed a comprehensive analysis in 42 WM patients by using high-resolution array-based comparative genomic hybridization with the Human Genome 244A microarray. Overall, 83% of samples have chromosomal abnormalities, with a median of three abnormalities per patient (range 0 to 27). The most common abnormality was 6q deletion (40%) and four non-overlapped minimal deleted regions (MDR) were identified. Gain of 6p was the second most common abnormality (17%) and its presence was always concomitant with 6q loss. An interstitial MDR was delineated at 13q14 including MIRN15A and MIRN16-1 in 10% of patients. Other recurrent deletions were 7q22, 8p, 11q22-q23, 11q23-q24 and 17p11-p13 (7% each). Copy gains were identified in chromosomes 18 (17%), 4 (12%), 3 (10%), 8q (10%) and Xq27.1-q28 (10%). To note, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in TRAF3 and TNFAIP3, two negative regulators of the NF-kB signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kB target genes. Mutational activation of the NF-kB pathway, which is normally activated by ligand-receptor interactions within the bone marrow microenvironment, highlight its biologic importance, and suggest a therapeutic role for inhibitors of NF-KB pathway activation in the treatment of Waldenstrms macroglobulinemia.
Publication Title
Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples