NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma [RNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE328216 | GEO | 2026/07/15
REPOSITORIES: GEO
Similar Datasets
Project description:The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of multiple myeloma (MM) patients. Herein, we report the discovery of NSD2-LDD, a cereblon-recruiting and PWWP1-mediated ligand directed degrader (LDD) that selectively and potently eliminates full length and PWWP1 domain containing NSD2 protein. NSD2-LDD treatment induces global loss of H3K36me2 leading to promoter-proximal spreading of H3K27me3 and re-wiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease-associated phenotypes including stromal adhesion, three-dimensional colony growth and paracrine signaling. By integrating patient single cell profiles with model 3D epigenomic and spatial transcriptomics, we delineate t(4;14) disease state and the tumor-intrinsic reprogramming and resultant remodeling of the bone marrow microenvironment upon NSD2 degradation. In cell line derived xenografts and genetically engineered mouse models of t(4;14), NSD2-LDD extends median survival accompanied by tumoral H3K36me2 loss and niche re-modelling. Collectively, this work validates NSD2 as a tractable dependency and supports clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM.
2026-07-15 | GSE328215 | GEO
Project description:This study aimed to identify the direct transcriptional targets of the H3K36me2 methyltransferase NSD2 in t(4;14) multiple myeloma (MM), where its aberrant expression drives oncogenesis, and to elucidate the molecular mechanisms underlying its regulatory role. To achieve this with precise temporal control and minimize cellular adaptation artifacts, we established an inducible dTAG-mediated acute NSD2 degradation system in the KMS-11 t(4;14) MM cell line. Using this model, we performed time-resolved SLAM-seq to measure newly synthesized mRNA levels at 7, 14, and 21 days post-NSD2 degradation, enabling the identification of primary transcriptional targets. Further SLAM-seq datasets were generated under conditions of NSD2 depletion followed by reconstitution with either wild-type NSD2 (NSD2WT) or a catalytically inactive mutant (NSD2Y1179A) to evaluate the requirement for SET domain activity. The contribution of H3K27me3 antagonism to NSD2-mediated gene regulation was investigated by performing SLAM-seq on NSD2-depleted cells treated with distinct PRC2 inhibitors (EPZ-6438 and MAK-658). Complementing the transcriptomic data, we performed CUTTAG to map the genomic distribution of the H3K27me3 histone mark following NSD2 depletion relative to control conditions. Analysis of these datasets revealed 308 primary NSD2 transcriptional targets, predominantly downregulated upon NSD2 loss and enriched for functionally relevant transcription factors. Reconstitution experiments demonstrated that NSD2's transcriptional effects are almost entirely dependent on its SET domain catalytic activity. Furthermore, PRC2 inhibition partially rescued the downregulation of approximately half of the NSD2 target genes, highlighting a significant role for H3K27me3 antagonism. Importantly, CUTTAG analysis showed that the compensatory increase in H3K27me3 upon NSD2 loss occurred primarily across genome-wide intergenic regions, rather than directly at the promoters or gene bodies of NSD2 target genes. Collectively, these deposited transcriptomic (SLAM-seq) and epigenomic (H3K27me3 CUTTAG) data support a model where NSD2 regulates target gene transcription via H3K36me2 deposition, which, in part, functions by antagonizing H3K27me3 deposition at distal regulatory elements to foster a permissive chromatin environment, providing a valuable resource for understanding NSD2 function in t(4;14) MM and Wolf-Hirschhorn syndrome.
2026-07-01 | GSE294275 | GEO
Project description:This study aimed to identify the direct transcriptional targets of the H3K36me2 methyltransferase NSD2 in t(4;14) multiple myeloma (MM), where its aberrant expression drives oncogenesis, and to elucidate the molecular mechanisms underlying its regulatory role. To achieve this with precise temporal control and minimize cellular adaptation artifacts, we established an inducible dTAG-mediated acute NSD2 degradation system in the KMS-11 t(4;14) MM cell line. Using this model, we performed time-resolved SLAM-seq to measure newly synthesized mRNA levels at 7, 14, and 21 days post-NSD2 degradation, enabling the identification of primary transcriptional targets. Further SLAM-seq datasets were generated under conditions of NSD2 depletion followed by reconstitution with either wild-type NSD2 (NSD2WT) or a catalytically inactive mutant (NSD2Y1179A) to evaluate the requirement for SET domain activity. The contribution of H3K27me3 antagonism to NSD2-mediated gene regulation was investigated by performing SLAM-seq on NSD2-depleted cells treated with distinct PRC2 inhibitors (EPZ-6438 and MAK-658). Complementing the transcriptomic data, we performed CUT&Tag to map the genomic distribution of the H3K27me3 histone mark following NSD2 depletion relative to control conditions. Analysis of these datasets revealed 308 primary NSD2 transcriptional targets, predominantly downregulated upon NSD2 loss and enriched for functionally relevant transcription factors. Reconstitution experiments demonstrated that NSD2's transcriptional effects are almost entirely dependent on its SET domain catalytic activity. Furthermore, PRC2 inhibition partially rescued the downregulation of approximately half of the NSD2 target genes, highlighting a significant role for H3K27me3 antagonism. Importantly, CUT&Tag analysis showed that the compensatory increase in H3K27me3 upon NSD2 loss occurred primarily across genome-wide intergenic regions, rather than directly at the promoters or gene bodies of NSD2 target genes. Collectively, these deposited transcriptomic (SLAM-seq) and epigenomic (H3K27me3 CUT&Tag) data support a model where NSD2 regulates target gene transcription via H3K36me2 deposition, which, in part, functions by antagonizing H3K27me3 deposition at distal regulatory elements to foster a permissive chromatin environment, providing a valuable resource for understanding NSD2 function in t(4;14) MM and Wolf-Hirschhorn syndrome.
2026-04-01 | GSE294271 | GEO
Project description:Recurrent chromosomal translocations are central to the pathogenesis of multiple myeloma (MM), with t(4;14) translocation being the second-most common and associated with poor prognosis. The nuclear receptor-binding SET domain 2 (NSD2) is overexpressed as a result of the translocation and has been suggested to be the primary oncogenic factor in t(4;14) MM. However, the detailed oncogenic mechanism of NSD2 in MM is still not completely understood. To address the relevant pathways downstream of NSD2 that contributes to myelomagenesis, SILAC-based mass-spectrometry analysis was used to determine NSD2-interacting proteins. We identified 74 proteins and in silico analysis showed that one of them, SMARCA2, interacts with NSD2. Comparison of SMARCA2 expression across MM cell lines with different translocation statuses showed that SMARCA2 was highly expressed in t(4;14) MM cells but not in non-t(4;14) MM cells. SMARCA2 knockdown in t(4;14) MM cells showed reduced cell growth and capacity to form colonies. We further investigated how NSD2 and SMARCA2 regulate the expressions of key myeloma genes, such as PRL3 and CCND1. This study reveals a spectrum of NSD2-interacting proteins involved in different biological pathways, indicating the importance of NSD2 in t(4;14) MM. The interaction between NSD2 and SMARCA2 in regulating the expression of CCND1 and PRL3 suggests the potential of SMARCA2 as a novel therapeutic target for t(4;14) MM.
2021-07-15 | GSE140860 | GEO
Project description:NSD2 is a histone methyltransferase that specifically dimethylates histone H3 lysine 36 (H3K36me2), a modification associated with gene activation. Dramatic overexpression of NSD2 in t(4;14) multiple myeloma (MM) and an activating mutation of NSD2 discovered in acute lymphoblastic leukemia (ALL) are significantly associated with altered gene activation, transcription and DNA damage repair. The partner proteins through which NSD2 may influence critical cellular processes remain poorly defined. In this study, we utilized proximity-based labelling (BioID) combined with label-free quantitative mass spectrometry to identify high confidence NSD2 interacting partners in MM cells.
2019-06-27 | PXD013759 | Pride
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 and t(4;14) translocation knockout (TKO) cells. Each cell line is tested in triplicate.
2011-11-29 | E-GEOD-29148 | biostudies-arrayexpress
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of KMS11 cells stably transduced with control vector in comparison to two independent shRNAs against NSD2. Each cell line is tested in duplicate.
2011-11-29 | E-GEOD-29147 | biostudies-arrayexpress
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. Genome-wide expression profiling of p19ARF-/- mouse embryonic fibroblasts stably transduced with control vector or wild-type NSD2. Each cell line is tested in triplicate.
2011-11-29 | E-GEOD-29150 | biostudies-arrayexpress
Project description:NSD2 (also named MMSET and WHSC1) is a histone lysine methyltransferase that is implicated in diverse diseases and commonly overexpressed in multiple myeloma due to a recurrent t(4;14) chromosomal translocation. However, the precise catalytic activity of NSD2 is obscure, preventing progress in understanding how this enzyme influences chromatin biology and myeloma pathogenesis. Here we show that dimethylation of histone H3 at lysine 36 (H3K36me2) is the principal chromatin-regulatory activity of NSD2. Catalysis of H3K36me2 by NSD2 is sufficient for gene activation. In t(4;14)-positive myeloma cells, the normal genome-wide and gene-specific distribution of H3K36me2 is obliterated, creating a chromatin landscape that selects for a transcription profile favorable for myelomagenesis. Catalytically active NSD2 confers xenograft tumor formation and invasion capacity upon t(4;14)-negative cells and NSD2 promotes oncogenic transformation of primary cells in an H3K36me2-dependent manner. Together our findings establish H3K36me2 as the primary product generated by NSD2, and demonstrate that genomic disorganization of this canonical chromatin mark initiates oncogenic programming. ChIP sequencing of H3K36me2 ChIP DNA from KMS11 and TKO2 cells using Illumina Solexa Genome Analyzer II single end sequencing protocol. The experiment contains two biological replicates of H3K36me2 ChIP DNA and input materials from KMS11 and TKO2 cells.
2011-11-29 | E-GEOD-29146 | biostudies-arrayexpress
Project description:Multiple myeloma (MM) cells undergo metabolic reprogramming in response to a hypoxic and nutrient-deprived bone marrow microenvironment. However, it is unclear whether primary oncogenes in recurrent translocations drive metabolic heterogeneity that can present new vulnerabilities for therapeutic targeting. t(4;14) translocation leads to the universal overexpression of histone methyltransferase MMSET II that promotes plasma cell transformation through a global increase in H3K36me2. We identified PKCα as a novel epigenetic target that contributes to the oncogenic potential of MMSET II. RNA-sequencing of t(4;14) cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCα, and the glycolytic gene, hexokinase 2 (HK2), is transcriptionally regulated by PKCα in a PI3K/Akt-dependent manner. Loss of PKCα displaces mitochondria-bound HK2 and reversed sensitivity towards the glycolytic blocker 3-Bromopyruvate. Additionally, we observed a metabolic shift to a less energetic state through the reduction in oxidative and glycolytic fluxes, resulting in an overall decrease in ATP production. We employed metabolomics and lactate emerged as a differential metabolite associated with PKCα. This conferred PKCα with immunomodulatory drug (IMiDs) resistance in a cereblon-independent manner and could be phenocopied by either overexpression of HK2 or direct supplementation of lactate. Altogether, we revealed novel insights into the epigenetic and metabolism crosstalk in MM and the opportunity for therapeutic intervention that leverages on the distinct metabolic program in t(4;14) myeloma.
2022-07-26 | GSE208739 | GEO