NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE199754 | GEO | 2023/01/13
REPOSITORIES: GEO
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Project description:The NSD2 p.E1099K (EK) mutation increases methyltransferase activity and is observed in 10% of acute lymphoblastic leukemia (ALL) samples with enrichment at relapse indicating a role in clonal evolution and drug resistance. To discover mechanisms that mediate the clonal expansion, we engineered B-ALL cell lines (Reh, 697) to overexpress wildtype (WT) and EK NSD2, but observed no differences in proliferation, clonal growth, or chemosensitivity. To address whether NSD2 EK acts collaboratively with other pathways, we used shRNAs to knockdown expression of NSD2 in B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM). Knockdown resulted in decreased proliferation in all three lines, decreased clonal growth in RCH-ACV, and increased sensitivity to chemotherapeutic agents routinely used in ALL therapy, although the pattern of drug sensitivity varied among cell lines implying that the oncogenic properties of NSD2 mutations are likely cell context specific and rely on cooperative pathways to exert its effect. Knockdown of both Type II and REIIBP EK isoforms had a greater impact than knockdown of Type II alone, suggesting that both SET containing EK isoforms contribute to phenotypic changes driving relapse. Furthermore, in vivo models using both cell lines and patient samples revealed dramatically enhanced proliferation of NSD2 EK compared to WT and reduced sensitivity to 6-mercaptopurine in the relapse sample relative to diagnosis. Finally, EK-mediated changes in chromatin state and transcriptional output differed dramatically among cell lines further supporting a cell context specific role of NSD2 EK. These results demonstrate a unique role of NSD2 EK in mediating clonal fitness through pleiotropic mechanisms dependent on the genetic and epigenetic landscape.
2020-04-23 | GSE149158 | GEO
Project description:The NSD2 p.E1099K (EK) mutation increases methyltransferase activity and is observed in 10% of acute lymphoblastic leukemia (ALL) samples with enrichment at relapse indicating a role in clonal evolution and drug resistance. To discover mechanisms that mediate the clonal expansion, we engineered B-ALL cell lines (Reh, 697) to overexpress wildtype (WT) and EK NSD2, but observed no differences in proliferation, clonal growth, or chemosensitivity. To address whether NSD2 EK acts collaboratively with other pathways, we used shRNAs to knockdown expression of NSD2 in B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM). Knockdown resulted in decreased proliferation in all three lines, decreased clonal growth in RCH-ACV, and increased sensitivity to chemotherapeutic agents routinely used in ALL therapy, although the pattern of drug sensitivity varied among cell lines implying that the oncogenic properties of NSD2 mutations are likely cell context specific and rely on cooperative pathways to exert its effect. Knockdown of both Type II and REIIBP EK isoforms had a greater impact than knockdown of Type II alone, suggesting that both SET containing EK isoforms contribute to phenotypic changes driving relapse. Furthermore, in vivo models using both cell lines and patient samples revealed dramatically enhanced proliferation of NSD2 EK compared to WT and reduced sensitivity to 6-mercaptopurine in the relapse sample relative to diagnosis. Finally, EK-mediated changes in chromatin state and transcriptional output differed dramatically among cell lines further supporting a cell context specific role of NSD2 EK. These results demonstrate a unique role of NSD2 EK in mediating clonal fitness through pleiotropic mechanisms dependent on the genetic and epigenetic landscape.
2020-04-23 | GSE149157 | GEO
Project description:The NSD2 p.E1099K (EK) mutation increases methyltransferase activity and is observed in 10% of acute lymphoblastic leukemia (ALL) samples with enrichment at relapse indicating a role in clonal evolution and drug resistance. To discover mechanisms that mediate the clonal expansion, we engineered B-ALL cell lines (Reh, 697) to overexpress wildtype (WT) and EK NSD2, but observed no differences in proliferation, clonal growth, or chemosensitivity. To address whether NSD2 EK acts collaboratively with other pathways, we used shRNAs to knockdown expression of NSD2 in B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM). Knockdown resulted in decreased proliferation in all three lines, decreased clonal growth in RCH-ACV, and increased sensitivity to chemotherapeutic agents routinely used in ALL therapy, although the pattern of drug sensitivity varied among cell lines implying that the oncogenic properties of NSD2 mutations are likely cell context specific and rely on cooperative pathways to exert its effect. Knockdown of both Type II and REIIBP EK isoforms had a greater impact than knockdown of Type II alone, suggesting that both SET containing EK isoforms contribute to phenotypic changes driving relapse. Furthermore, in vivo models using both cell lines and patient samples revealed dramatically enhanced proliferation of NSD2 EK compared to WT and reduced sensitivity to 6-mercaptopurine in the relapse sample relative to diagnosis. Finally, EK-mediated changes in chromatin state and transcriptional output differed dramatically among cell lines further supporting a cell context specific role of NSD2 EK. These results demonstrate a unique role of NSD2 EK in mediating clonal fitness through pleiotropic mechanisms dependent on the genetic and epigenetic landscape.
2020-04-23 | GSE149155 | 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:RCH-ACV cells was depleted for SETDB2 by shRNA lentivirus construct co-expressing mCherry fluorescent. After sorting of mCherry positive cells, the cells were cultured and expanded and total RNA was extracted for Microarray experiment.
2019-01-19 | GSE125329 | GEO
Project description:The epigenetic plasticity, such as DNA methylation and histone modification, has been suggested to be a potential mechanism controlling MM progression and drug resistance, but the underlying mechanisms are not fully understood. Here we demonstrate that some drug resistant genes were activated during myeloma resistance to bortezomib. Mechanistically, Aurora A can interact with NSD2, whose SET domain is responsible to H3K36me2 to enhance the transcriptional activity of Aurora A target gene. Once Aurora A is knocked out, H3K36me2 activity will change, changing the transcription activity of those drug resistant genes.
2020-12-22 | GSE163589 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE29146: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [ChIP] GSE29147: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [RNAi] GSE29148: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [TKO] GSE29150: NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming [Transduction] Refer to individual Series
2011-11-29 | E-GEOD-29305 | 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. 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