Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Immune-aging is linked to clinical malignancy and vaccine responses in myeloma

ABSTRACT: Several single-cell transcriptomic approaches have been applied to study immune system in MM, and previously implied “T-cell exhaustion” largely based on comparison with signatures derived in murine chronic viral infection models. However functional validation of such “signatures” has been lacking. In this paper, we have studied nearly 300+ racially diverse MM/MGUS patients/healthy controls. Initial functional studies did not support global T cell exhaustion, but instead illustrated paradoxically enhanced inflammatory cytokine production and proliferation in MM T cells, even in phenotypes previously thought to be “exhausted”. We therefore hypothesized that altered states of T cell differentiation (e.g. increased terminal effectors) may instead be related to immune aging. In order to quantify this, we first studied a cohort of 100+ healthy donors across 7 decades of life to quantify age-associated immune changes, and then applied findings to MM/MGUS cohorts. This led to the discovery that in chronologically age-matched cohorts, MM is associated with greater immune aging compared to MGUS. These findings were also supported by transcriptomic and phospho-proteomic analyses. Interestingly, MGUS patients with Black ancestry exhibited enhanced aging. These data therefore support potential contribution of immune aging in malignant transformation, as well as racial predisposition with earlier onset of MM in Blacks. Finally, to evaluate the impact of immune aging on immune function in vivo, we analyzed yet another cohort of patients undergoing SARSCov2 vaccination. Immune but not chronologic aging was associated with responses to vaccination.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288020 | GEO | 2025/01/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling by microarray of High-density neutrophils in multiple myeloma and monoclonal gammopathy patients compared to healthy donors.

Project description:Multiple Myeloma (MM) is a plasma cell malignancy with a well- documented immune dysfunction. We previously showed that granulocyte-myeloid derived suppressor cells (G-MDSC) are increased in MM thus to contribute to refractoriness to lenalidomide. MM-, differently from MGUS, mesenchymal cells lead myeloid precursors to acquire G-MDSC phenotype, suggesting that MM-microenvironment can affect myeloid maturation. Because there is a phenotypic overlapping between G-MDSC and mature high-density neutrophils (HDN), we investigated functionally HDN to gauge their contribution in immune-suppression in patients affected by monoclonal gammopathy of uncertain significance (MGUS) and symptomatic MM.

2020-01-20 | E-MTAB-6105 | biostudies-arrayexpress

Primary bone marrow stromal cells in plasma cell disorders

Project description:Multiple myeloma (MM) and its premalignant precursor MGUS (monoclonal gammopathy of undetermined significance) are clonal plasma cell diseases that develop in the bone marrow (BM) and are dependent on microenvironmental interactions. Primary bone marrow stromal cells (BMSCs) are key players in the BM microenvironment, however, their role in MGUS/MM pathophysiology is not known. We therefore investigated potential disease-specific alterations in prospectively isolated BMSCs from MM, MGUS and healthy controls. Clear disease-related BMSC surface marker and gene expression differences were recorded, and deep sequencing identified shared MGUS/MM as well as MM-specific molecular signatures. Moreover, we identified genes that were deregulated in a disease-stage manner, thus reflecting the progression from normal to MGUS and MM. Analysis of primary BMSCs revealed disease-stage related protein and gene expression patterns, which provides novel insight into the stromal transitions and their functional implications for plasma cell disease development and progression.

2024-01-31 | GSE129801 | GEO

Genome-wide profiling of copy-number alteration in monoclonal gammopathy of undetermined significance

Project description:Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition with an approximate 1% annual risk of symptomatic plasma cell disorder development, mostly to multiple myeloma (MM). We performed genome-wide screening of copy-number alterations (CNAs) in 90 MGUS and 33 MM patients using high-density DNA microarrays. We identified CNAs in a smaller proportion of MGUS (65.6%) than in MM (100.0%, p=1.31×10-5) and showed median number of CNAs is lower in MGUS (3, range 0-22) than in MM (13, range 4-38, p=1.82×10-10). In the MGUS cohort, the most frequent losses were located at 1p (5.6%), 6q (6.7%), 13q (30.0%), 14q (14.4%), 16q (8.9%), 21q (5.6%) and gains at 1q (23.3%), 2p (6.7%), 6p (13.3%) and Xq (7.8%). Hyperdiploidy was detected in 38.9% of MGUS cases and the most frequent whole chromosome gains were 3 (25.6%), 5 (23.3%), 9 (37.8%), 15 (23.3%) and 19 (32.2%). We also identified CNAs such as 1p, 6q, 8p, 12p, 13q, 16q losses, 1q gain and hypodiploidy, which are potentially associated with an adverse prognosis in MGUS. In summary, we showed that MGUS is similar to MM in that it is a genetically heterogeneous disorder, but overall cytogenetic instability is lower than in MM, which confirms that genetic abnormalities play important role in monoclonal gammopathies.

2016-02-18 | GSE77975 | GEO

Loss of the Inhibitory Immune Checkpoint CD85j/LILRB1 on Malignant Plasma Cells Contributes to Immune Escape in Multiple Myeloma

Project description:Mechanisms of immune regulation may control proliferation of aberrant plasma cells (PCs) in patients with the asymptomatic monoclonal gammopathy of undetermined significance (MGUS) preventing progression to active multiple myeloma (MM). We investigated the role of CD85j (LILRB1), an inhibitory immune checkpoint for B cell function, in MM pathogenesis. We used microarrays to gain insight into the molecular mechanisms underlying CD85j functions in myeloma cells.

2016-11-14 | GSE89793 | GEO

Expression data of plasma cell from MGUS patients

Project description:Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Serum markers are currently used to stratify MGUS patients into clinical risk groups. A molecular signature predicting MGUS progression has not been produced. We have explored the use of gene expression profiling to risk-stratify MGUS and developed an optimized signature based on large samples with long-term follow-up. Microarray analysis of mRNA from MGUS patients with stable disease and MGUS patients that progressed to MM within 10 years, was used to define a molecular signature of MGUS risk.

2023-08-15 | GSE235356 | GEO

The Differentiation and Stress Response Factor, XBP-1, Drives Multiple Myeloma Pathogenesis

Project description:Multiple myeloma (MM) evolves from highly prevalent premalignant condition termed Monoclonal Gammopathy of Undetermined Significance (MGUS). We report an MGUS-MM phenotype arising in transgenic mice with Emu-directed expression of the unfolded protein/ER stress response and plasma cell development spliced isoform factor XBP-1s. Emu-XBP-1s elicited elevated serum Ig and IL-6 levels, skin alterations and with advancing age, a significant proportion of Emu-xbp-1s transgenic mice develop features diagnostic of human MM including bone lytic lesions. Transcriptional profiles of Emu-xbp-1s B lymphoid and MM cells show aberrant expression of genes known to be dysregulated in human MM including Cyclin D1, MAF, MAFB, and APRIL. This genetic model coupled with documented frequent XBP-1s overexpression in human MM serve to implicate chronic XBP-1s dysregulation in the development of this common and lethal malignancy. Keywords: XBP-1, MGUS, multiple myeloma, transgenic mouse

2007-04-09 | GSE6980 | GEO

New insights into hypoxia-driven metabolic, anti-apoptotic and immune evasion strategies of primary human myeloma cells

Project description:Multiple Myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). It develops from a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage, smoldering MM (SMM). The mechanisms of MM progression have not yet been fully understood, all the more because patients with MGUS and SMM already carry the same initial mutations found in MM cells. Over the last years, more and more importance has been attributed to the tumor microenvironment and its role in the pathophysiology of the disease. Adaptations of MM cells to the hypoxic conditions in the BM have been shown to contribute to a significant extent to MM progression, independently from the genetic predispositions of the tumor cells. To get deeper insights into such hypoxia-induced adaptations, we decided to investigate primary human MM cells. CD138-positive plasma cells freshly isolated from the BM of patients with different disease stages, comprising MGUS, SMM, and MM, were analyzed by proteome profiling using a Q Exactive orbitrap. Data previously obtained from peripheral B cells were included for comparative purposes. As a first, rather unexpected result, we were able to identify three clusters differentiating B cells as well as MM cells corresponding to less and more advanced disease stages. Comparing on the one hand B cells to MM cells, and on the other hand the two clusters of MM cells allowed us to determine transcription factors apparently involved in MM development and progression, as well as protein regulatory networks obviously related to metabolic adaptations and immune evasion strategies used by MM cells to overcome limitations imposed by hypoxia. Based on these results, new opportunities may arise for developing therapeutic strategies targeting the progression from less to more advanced stages of MM.

2019-02-27 | PXD010600 | Pride

Somatic mutation spectrum in monoclonal gammopathy of undetermined significance indicates a simpler genomic landscape compared to multiple myeloma

Project description:Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma (MM) with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about the molecular mechanism of malignant transformation. We have performed whole-exome sequencing together with CGH+SNP array analysis in 33 flow-cytometry separated abnormal plasma cell samples from MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations and copy-number alterations were present in 97.0% and in 60.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in MGUS compared to MM (p<10-4) and we have identified six genes that are significantly mutated in MM (KRAS, NRAS, DIS3, HIST1H1E, EGR1 and LTB) in the MGUS dataset. We also found a positive correlation with increasing chromosome changes and somatic mutations. IGH translocations were present in 27.3% of cases comprising t(4;14), t(11;14), t(14;16) or t(14;20) and were in a similar frequency to MM, which corresponded with the primary lesion hypothesis. Data from this study showed MGUS is a genetically comprehensive disease, however, overall genetic instability is significantly lower compared to MM.

2016-02-18 | GSE77979 | GEO

Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

Project description:To gain further insights into the role of the transcriptome deregulation in the transition from a normal plasma cell (NPC) to a clonal PC and from an indolent clonal PC to a malignant PC, we performed gene expression profiling in 20 patients with MGUS, 33 with high-risk SMM and 41 with MM. The analysis showed that 126 genes were differentially expressed in MGUS, SMM and MM as compared to NPC. Interestingly, 17 and 9 out of the 126 significant differentially expressed genes were small nucleolar RNA molecules (snoRNA) and zinc finger proteins. GADD45A was the most significant up-regulated gene in clonal PC compared to NPC. Several proapoptotic genes (AKT1 and AKT2) were downregulated and antiapoptotic genes (APAF1 and BCL2L1) were upregulated in MM, both symptomatic and asymptomatic, compared to MGUS. Myc mediated apoptosis signaling is one of the top canonical pathways differentiating the asymptomatic and symptomatic myeloma. When we looked for those genes progressively modulated through the evolving stages of monoclonal gammopathies, eight snoRNA showed a progressive increase while APAF1, VCAN and MEGF9 exhibited a progressive downregulation in the transition from MGUS to SMM and to MM. In conclusion, our data show that although MGUS, SMM and MM are not clearly distinguishable groups according to their GEP, several signaling pathways and genes were significant deregulated in the different steps of transformation process.

2014-05-22 | GSE47552 | GEO

Gene expression of bone marrow fibroblasts from monoclonal gammopathy of undetermined significance and active multiple myeloma

Project description:Fibroblasts are a key cellular component of tumour microenvironment, along with other stromal cells playing a critical role in disease initiation and progression (1). In this study, bone marrow fibroblasts deriving from patients with monoclonal gammopathy of undetermined significance (MGUS) or active multiple myeloma (MM) were subjected to global gene expression analysis, in order to identify progression-associated alterations of gene expression. Through immunoselection procedures, primary cultures of bone marrow fibroblasts were established from bone marrow aspirate of 18 patients fullfilling the International Myeloma Working Group diagnostic criteria for MM (n=10) and MGUS (n=8). Differentially expressed genes were investigated through cDNA microarray (21,329 70-mer oligonucleotides; dual-label competitive hybridization), using the reference design as experimental protocol and t-test statistics for identifying differentially expressed genes. A number of genes functionally involved in survival, proliferation, motility, inflammation and angiogenesis were found to be up-regulated in bone marrow fibroblasts from MM patients with respect to MGUS patients. In parallel, several genes were down-regulated in MM fibroblasts. Overall, bone marrow fibroblasts from MM patients show a distinct gene expression pattern that differentiates them from bone marrow fibroblasts of MGUS. The observation of differentially expressed genes indicates an activation state of fibroblasts in MM, which very likely concur to determine a microenvironment supporting disease progression. 1. Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer 2006; 6: 392:401.

2010-10-30 | GSE24990 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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