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Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242505 | GEO | 2024/08/09

REPOSITORIES: GEO

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Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [ChIP-seq]

Project description:Multiple myeloma (MM) is a malignant B cell dyscrasia characterized by the accumulation of clonal plasma cells (PC) within the bone marrow. Epigenetic factors are involved in MM initiation, progression, and occurrence of chemoresistance. Among them EZH2, the Polycomb Repressive Complex 2 (PRC2) catalytic subunit and NSD2 (MMSET), the target oncogene of t(4;14) primary translocation, are both associated with poor prognosis values and contribute to MM disease. In this study, we identified a physical interaction between EZH2 and MMSET in MM. We used MMSET-depleted MM cells and MAK-683, an allosteric inhibitor of EZH2, to disrupt this interaction and understand its implication in MM biology and resistance to anti-MM drugs. Through its interaction with EZH2, MMSET regulates PRC2 nuclear localization in MM cells, promotes a particularly poor prognosis in MM patients, and modulates the expression of tumor-suppressor genes involved in p53 pathway. We also demonstrated that MAK-683 can interfere with this interaction and synergizes with conventional drugs used in MM treatment: Melphalan, an alkylating agent triggering DNA Damage Response (DDR); and Panobinostat, a Histone De-Acetylase (HDAC) inhibitor directedly regulating p53 acetylation and stability.

2024-08-09 | GSE242500 | GEO

Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [RNA-seq]

2024-08-09 | GSE242451 | GEO

Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology

Project description:Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology

| PRJNA1013589 | ENA

Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [RNA-seq]

Project description:Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [RNA-seq]

| PRJNA1013496 | ENA

Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [ChIP-seq]

Project description:Epigenetic modifiers MMSET and EZH2 physically interact and cooperate to support Multiple Myeloma pathophysiology [ChIP-seq]

| PRJNA1013595 | ENA

MMSET alters EZH2 Binding in Myeloma Cells

Project description:We investigated EZH2 binding in the presence and absence of MMSET protein. MMSET overexpression in t(4;14)+ myeloma leads to global loss of H3K27 methylation and redistribution of EZH2 binding throughout the genome

2014-09-01 | GSE57632 | GEO

MMSET alters EZH2 Binding in Myeloma Cells

2014-09-01 | E-GEOD-57632 | biostudies-arrayexpress

Impact of Genes Highly Correlated with MMSET Myeloma on the Survival of Non-MMSET Myeloma Patients.

Project description:PURPOSE:The poor prognosis of multiple myeloma with t(4;14) is driven by the fusion of genes encoding multiple myeloma SET domain (MMSET) and immunoglobulin heavy chain. Specific genes affected by MMSET and their clinical implications in non-MMSET myeloma remain undetermined. EXPERIMENTAL DESIGN:We obtained gene expression profiles of 1,032 newly diagnosed myeloma patients enrolled in Total Therapy 2, Total Therapy 3, Myeloma IX, and HOVON65-GMMGHD4 trials and 156 patients from Multiple Myeloma Resource Collection. Probes that correlated most with MMSET myeloma were selected on the basis of a multivariable linear regression and Bonferroni correction and refined on the basis of the strength of association with survival in non-MMSET patients. RESULTS:Ten MMSET-like probes were associated with poor survival in non-MMSET myeloma. Non-MMSET myeloma patients in the highest quartile of the 10-gene signature (MMSET-like myeloma) had 5-year overall survival similar to that of MMSET myeloma [highest quartile vs. lowest quartile HR = 2.0; 95% confidence interval (CI), 1.5-2.8 in MMSET-like myeloma; HR = 2.3; 95% CI, 1.6-3.3 in MMSET myeloma]. Analyses of MMSET-like gene signature suggested the involvement of p53 and MYC pathways. CONCLUSIONS:MMSET-like gene signature captures a subset of high-risk myeloma patients underrepresented by conventional risk stratification platforms and defines a distinct biologic subtype. Clin Cancer Res; 22(16); 4039-44. ©2016 AACR.

| S-EPMC5576175 | biostudies-literature

Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T(4;14) multiple myeloma.

Project description:Multiple myeloma (MM) is characterized by recurrent chromosomal translocations. MMSET, identified by its fusion to the IgH locus in t(4;14) MM, is universally overexpressed in t(4;14) MM. In order to identify cell surface biomarkers associated with t(4;14) MM for small molecule or antibody based therapies, we knocked down MMSET expression with shRNA and generated a cell line pair from KMS11, a t(4;14) MM cell line. We used quantitative mass spectrometry to identify plasma membrane proteins associated with MMSET overexpression. Using this approach, 50 cell surface proteins were identified as differentially expressed between KMS11 and KMS11/shMMSET. Western blot and flow cytometry analysis indicated SLAMF7 was over-expressed in t(4;14) MM cell lines and down-regulated by MMSET shRNAs. SLAMF7 expression was also confirmed in primary t(4;14) MM samples by flow cytometry analysis. Quantitative RT-PCR and ChIP analysis indicated MMSET might regulate the transcription level of SLAMF7 and be an important functional element for SLAMF7 promoter activity. Furthermore, SLAMF7 shRNA could induce G1 arrest or apoptosis and reduce clonogenetic capacity in t(4;14) MM cells. Overall, these results illustrated SLAMF7 might be a novel cell surface protein associated with t(4;14) MM. It is potential to develop t(4;14) MM targeted therapy by SLAMF7 antibody mediated drug delivery.

| S-EPMC3759662 | biostudies-literature

Effects of MMSET on gene expression in multiple myeloma

Project description:The MMSET (Multiple Myeloma SET domain) protein is overexpressed in multiple myeloma patients with the translocation t(4;14). Although studies have shown the involvement of MMSET/WHSC1 in development, its mode of action in the pathogenesis of multiple myeloma (MM) is largely unknown. We found that MMSET is a major regulator of chromatin structure and transcription in t(4;14) MM cells. High levels of MMSET correlate with an increase in lysine 36 methylation of histone H3 and a decrease in lysine 27 methylation across the genome, leading to a more open structural state of the chromatin. Loss of MMSET expression alters adhesion properties, suppresses growth and induces apoptosis in MM cells. Consequently, genes affected by high levels of MMSET are implicated in the p53 pathway, cell cycle regulation and integrin signaling. Regulation of many of these genes required functional histone methyl-transferase (HMT) activity of MMSET. These results implicate MMSET as a major epigenetic regulator in t(4;14)+ MM.

2010-10-20 | GSE24746 | GEO

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