Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

ABSTRACT: Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years. To better understand and identify these ‘high-risk’ cases, we analyzed the translocation landscape of myeloma from 795 newly-diagnosed patients by whole genome sequencing from the CoMMpass study. Translocations involving the immunoglobulin lambda (IgL) locus were identified in 10% of patients, and were indicative of poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, potentially resulting in the misclassification of IgL-translocated myeloma. Most IgL-translocations coincided with focal amplifications that were centered on the 3’ enhancer. Patients with IgL-translocations failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor IKZF1 that is bound to the IgL 3’ enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL-translocation as a driver of poor prognosis which may be due in part to IMID resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121912 | GEO | 2019/03/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

ATAC-seq of Multiple Myeloma

Project description:Purpose: Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization of myeloma has identified subtypes with prognostic and therapeutic implications. In contrast, relatively little is known about the myeloma epigenome. Experimental Design: CD138+CD38+ myeloma cells were isolated from fresh bone marrow aspirate or the same aspirate after freezing for one to six months. Gene expression and chromatin accessibility were compared between fresh and frozen samples by RNA-seq and ATAC-seq. Chromatin accessible regions were used to identify regulatory RNA expression in over 700 samples from newly diagnosed patients in the MMRF CoMMpass trial (NCT01454297). Results: Gene expression and chromatin accessibility of cryopreserved myeloma recapitulated that of freshly isolated samples. ATAC-seq performed on a series of biobanked specimens identified thousands of chromatin accessible regions with hundreds being highly coordinated with gene expression. Over 4,700 of these chromatin accessible regions were transcribed in newly diagnosed myelomas from the CoMMpass trial. Regulatory element activity alone recapitulated myeloma gene expression subtypes, and in particular myeloma subtypes with IGH translocations were defined by transcription of distal regulatory elements. Moreover, enhancer activity predicted oncogene expression implicating gene regulatory mechanisms in aggressive myeloma. Conclusions: These data demonstrate the feasibility of using biobanked specimens for retrospective studies of the myeloma epigenome and illustrate the unique enhancer landscapes of myeloma subtypes that are coupled to gene expression and disease progression.

2021-03-03 | GSE167967 | GEO

RNA-seq of Multiple Myeloma

2021-03-03 | GSE167968 | GEO

Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

Project description:Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

| PRJNA499054 | ENA

Transcription profling of infants (<1 year of age) diagnosed with Acute Lymphoblastic Leukemia (ALL) characterised by genomic translocation.

Project description:Acute Lymphoblastic Leukemia (ALL) in infants (<1 year) is characterized by a poor prognosis and a high incidence of MLL translocations. Several studies demonstrated the unique gene expression profile associated with MLL-rearranged ALL, but generally small cohorts were analyzed as uniform patient groups regardless of the type of MLL translocation, while the analysis of translocation-negative infant ALL remained unacknowledged. We generated and analyzed primary infant ALL expression profiles (n=73) typified by translocations t(4;11), t(11;19) and t(9;11), or the absence of MLL translocations, in order to study translocation-specific gene expression between the different genetic subtypes of infant ALL.

2009-12-15 | E-GEOD-19475 | biostudies-arrayexpress

MMSET I acts as an oncoprotein and regulates GLO1 expression in t(4;14) multiple myeloma cells

Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. The translocation t(4;14)(p16;q32) is one of the most common translocation in MMs, affecting 15% of patients, and is associated with very poor prognosis. The histone methyltransferase (HMTase) MMSET is universally overexpressed in t(4;14) MM as a result of the t(4;14) translocation. MMSET is capable of producing 3 major isoforms, the full length MMSET II, short isoforms REIIBP and MMSET I. MMSET II has been suggested to play an important tumorigenic role in t(4;14) MM, but little is yet known about whether and how the MMSET short isoforms contribute to MM tumorigenesis. The aim of this study is to characterize MMSET I roles and determine its downstream targets in t(4;14) MM. In t(4;14) MM cells MMSET I knockdown with shRNAs induced cell apoptosis, reduced colony formation and inhibited tumorigenicity in vivo. We also found MMSET I knockdown decreased GLO1 expression, and ectopic MMSET I increased GLO1 expression, suggesting that MMSET I is an upstream regulator of GLO1. Further analysis indicated that MMSET I bound to GLO1 promoter region and depended on its C-terminus to regulate GLO1 expression. Our preliminary data suggested that MMSET I is an oncoprotein and could regulate GLO1 expression in t(4;14) multiple myeloma cells.

2019-01-01 | GSE98433 | GEO

Gain and/or amplification of chromosome 1q are frequently found in Multiple Myeloma (MM).

Project description:Background: Gain and/or amplification of chromosome 1q are frequently found in Multiple Myeloma (MM). The number of 1q copies correlates with a poor prognosis. The aim of this work is to study the impact on the clinical outcome and the trascriptomic changes induced by Gain1q (3 copies of 1q, 3X) and amplification 1q (Amp1q, ≥4 copies of 1q, 4X) in MM patients enrolled in the CoMMpass study (NCT145429). Methods: Fluorescence in situ hybridization (FISH) in CD138+ purified bone marrow plasma cells was centralized and performed at baseline. The cut-off level for Gain1q was 10% of nuclei with ≥3 copies of 1q (3X), while Amp1q was defined as ≥ 20% of nuclei with ≥4 copies of 1q (4X). Transcriptome data from patients were used to find differentially expressed genes (DEGs) in gain (3X) and amp1q (4X) patients.

2023-01-16 | GSE193427 | GEO

Translocations Activating IRF4 Identify a Subtype of Germinal-Center-Derived B-cell Lymphoma Affecting Predominantly Children and Young Adults

Project description:Background: Germinal center B-cell (GCB) lymphomas are common in children and adults. The prognosis strongly depends on age. Subgroups of GCB-lymphomas are characterized by chromosomal translocations affecting immunoglobulin (IG) loci leading to oncogene deregulation. Methods: Novel IG translocation partners were cloned within the network “Molecular Mechanisms in Malignant Lymphomas” (MMML) by long-distance inverse polymerase chain reaction. Mature aggressive B-cell lymphomas from the MMML as well as pediatric and adult lymphoma trials were analyzed by fluorescence in situ hybridization (FISH) and immunhistochemistry. Data from 438 MMML cases characterized by gene expression profiling were mined. Results: Cloning of unknown IG partners identified a t(6;14)(p25;q32) juxtaposing the IRF4 oncogene with the IGH-locus as novel recurrent aberration in GCB lymphoma. FISH analyses of 427 mature B-cell lymphomas for IRF4 translocations revealed 20 IG/IRF4 positive lymphomas (17 IGH/IRF4, 2 IGL/IRF4, 1 IGΚ/IRF4). IG/IRF4-positive lymphomas were predominantly GCB-type diffuse large B-cell lymphomas (DLBCL) or follicular lymphoma grade 3, shared overexpression of IRF4/MUM1 and BCL6 and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas was different from other subtypes of DLBCL and a classifier for IG/IRF4 positivity containing 27 genes allowed prediction of 3 additional MMML IG/IRF4-positive cases subsequently proven by FISH. IG/IRF4-positivity was associated with a favorable outcome likely due to significant enrichment of IG/IRF4-positive lymphomas in childhood and young adulthood. Conclusions: Our results suggest IRF4 translocations to be primary genetic alterations in a novel molecularly defined subset of GC-derived lymphomas predominantly affecting children. 271 diffuse large B-Cell lymphoma samples were hybridized to HGU133A Affymetrix GeneChips.

2011-06-24 | E-GEOD-22470 | biostudies-arrayexpress

Crosstalk between the glucocorticoid and mineralocorticoid receptor boosts glucocorticoid-induced killing of multiple myeloma cells

Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.

2023-10-24 | PXD043635 | Pride

Total protein abundances upon Mcm6 knockdown in the murine CH12 cells

Project description:Chromosomal translocations result from joining of DNA double-strand breaks (DSBs) and frequently cause cancer. Yet, the steps linking DSB formation to DSB ligation remain undeciphered. We report that DNA replication timing (RT) directly regulates lymphomagenic Myc translocations during antibody maturation in B-cells downstream of DSBs and independently of DSB frequency. Depletion of minichromosome-maintenance (MCM) complexes alters replication origin activity, decreases translocations and abrogates global RT. Ablating a single origin at Myc causes an early-to-late RT switch, loss of translocations and reduced nuclear proximity with a translocation partner locus, phenotypes that were reversed by restoring early RT. Disruption of shared early RT also reduced tumorigenic translocations in human leukemic cells. Thus, RT constitutes a new, unprecedented mechanism in translocation biogenesis linking DSB formation to DSB ligation

2022-09-13 | PXD034446 | Pride

Gene expression data from infants (<1 year of age) diagnosed with Acute Lymphoblastic Leukemia (ALL)

2009-12-16 | GSE19475 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data