Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukemia cells
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ABSTRACT:
PROVIDER: PRJNA514230 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8428602_1.fastq.gz | Fastqsanger.gz | |||
| SRR8428602_2.fastq.gz | Fastqsanger.gz | |||
| SRR8428603_1.fastq.gz | Fastqsanger.gz | |||
| SRR8428603_2.fastq.gz | Fastqsanger.gz | |||
| SRR8428604_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic modifiers were important players in the development of hematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyzes the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukemia progression and resistance to therapy targeting on BCR-ABL remain unclear. Here we found SETD2 acted as a tumor suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell’s imatinib sensitivity and enhanced the chemotherapeutic effect.
2019-07-19 | GSE124894 | GEO
Project description:ObjectivesEpigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.Materials and methodsThe level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34+ CD38- leukaemic stem cells by flow cytometry and colony formation assays upon SETD2 knockdown or overexpression. The impact of SETD2 expression alterations or small-molecule inhibitor JIB-04 targeting H3K36me3 loss on imatinib sensitivity was assessed by IC50, cell apoptosis and proliferation assays. Finally, RNA sequencing and ChIP-quantitative PCR were performed to verify putative downstream targets.ResultsSETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect.ConclusionsOur study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.
| S-EPMC6668982 | biostudies-literature
Project description:Inhibition of deregulated protein kinases by small molecule drugs has evolved into a major therapeutic strategy for the treatment of human malignancies. Imatinib mesylate has emerged as the leading compound to treat chronic myeloid leukemia (CML), through its inhibition of Bcr- Abl tyrosine kinases, and other cancers. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new BCR-ABL inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib showed large interest since the introduction of the nilotibin. To identify the cellular pathways affected by new synthesized compounds, we applied mass spectrometry together with stable isotope labeling by amino acids in cell culture (SILAC) for the comparative study of protein expression in K562 cells that were untreated or treated with imatinib and imatinib derivates. Further, the global proteome of the K562 cells treated with imatinib were quantitatively compared with the cells treated with the new compounds. This study enriched our knowledge about direct cellular targets of kinase selective drugs. Further the results offered important new knowledge for gaining insights into the structural effects of action of the new compounds. Samples were analyzed on a longer column (30cm) and a longer gradient (180min). Raw data files were processed with Mascot distiller 2.3. The mgf files were searched with Mascot daemon 2.3. The quantification was also done by Mascot Distiller. All data was stored in ms_lims. The manual validation of false peptide ratios was done with Rover (part of ms_lims). Fixed modifications: none. Variable modifications: acetylation of peptide N-terminus, pyroglutamate formation of N-terminal glutamine, methionine oxidation. Enzyme: trypsine with one missed cleavage allowed. Precursor mass tolerance: 10 ppm. Peptide fragment mass tolerance: 0.5 Da Quantitation method: SILAC arginine and lysine +6 Da. Overview of the 17 different analyses: B SK23 vs DMSO C Y22 vs DMSO D SK20 vs DMSO E Y18 vs DMSO I SK20 vs DMSO K Y18 vs DMSO O Y22 vs DMSO R Imatinib vs Water Z Imatinib vs Water J SK20 vs Imatinib M SK23 vs Imatinib N Y22 vs Imatinib P SK23 vs Imatinib Q Y18 vs Imatinib S Y22 vs Imatinib T SK20 vs Imatinib Y Y18 vs Imatinib
2014-06-30 | PXD000216 | Pride
Project description:SETD2 is a methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity occurs in some cancers, including renal cell carcinoma. SETD2 mutations have been linked to delayed transcription termination, but have not been explored in depth. Here, using nascent transcriptomics in SETD2 knockout and patient-derived cells, we reveal a dichotomy in SETD2 functions depending on the affected protein-coding gene. The majority of genes, named class I, are dependent on SETD2 function for transcription initiation, yet terminate transcription in the usual locations. In contrast, for class II genes, corresponding to 15-25% of active protein-coding genes, transcription initiation is robust in absence of SETD2 activity; however, widespread transcriptional readthrough occurs. Defective termination following SETD2 loss/mutation is associated with increased cryptic transcription initiation and impaired 3′ pre-mRNA cleavage. Additionally, alternative polyadenylation upon SETD2 activity loss is highly cell type specific, and no relationship with transcription readthrough was observed. We demonstrate that methyltransferase activity of SETD2 stimulates proper initiation, prevents cryptic initiation and promotes efficient 3′ end processing, however it does so indirectly.
2026-02-06 | GSE313082 | GEO
Project description:SETD2 is a methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity occurs in some cancers, including renal cell carcinoma. SETD2 mutations have been linked to delayed transcription termination, but have not been explored in depth. Here, using nascent transcriptomics in SETD2 knockout and patient-derived cells, we reveal a dichotomy in SETD2 functions depending on the affected protein-coding gene. The majority of genes, named class I, are dependent on SETD2 function for transcription initiation, yet terminate transcription in the usual locations. In contrast, for class II genes, corresponding to 15-25% of active protein-coding genes, transcription initiation is robust in absence of SETD2 activity; however, widespread transcriptional readthrough occurs. Defective termination following SETD2 loss/mutation is associated with increased cryptic transcription initiation and impaired 3′ pre-mRNA cleavage. Additionally, alternative polyadenylation upon SETD2 activity loss is highly cell type specific, and no relationship with transcription readthrough was observed. We demonstrate that methyltransferase activity of SETD2 stimulates proper initiation, prevents cryptic initiation and promotes efficient 3′ end processing, however it does so indirectly. This SuperSeries is composed of the SubSeries listed below.
2026-02-06 | GSE301929 | GEO
Project description:SETD2 is a key histone methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity has been implicated in various cancers, including renal cell carcinoma (RCC). In RCC, SETD2 mutations have been linked to defects in transcription termination, though the underlying mechanism remains unclear. Here, using nascent transcriptomics in SETD2 knockouts and RCC patient-derived cells, we show that SETD2 loss leads to delayed transcription termination, but only in a subset of genes. POINT-seq analysis reveals widespread transcriptional readthrough beyond canonical termination sites upon SETD2 loss/mutation, affecting 15–24% of genes. We demonstrate that defective termination following SETD2 loss/mutation is driven by a combination of increased cryptic transcription initiation and impaired 3′ pre-mRNA cleavage. In contrast, genes that maintain proper termination show significant downregulation. Additionally, we find that SETD2 ensures proper termination independently of alternative polyadenylation, underscoring the distinction between transcription termination and 3′ end processing. Our findings highlight that methyltransferase activity of SETD2 is a crucial regulator of transcriptional integrity, preventing cryptic initiation and promoting efficient 3′ end processing
2026-02-09 | GSE301039 | GEO
Project description:SETD2 is a key histone methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity has been implicated in various cancers, including renal cell carcinoma (RCC). In RCC, SETD2 mutations have been linked to defects in transcription termination, though the underlying mechanism remains unclear. Here, using nascent transcriptomics in SETD2 knockouts and RCC patient-derived cells, we show that SETD2 loss leads to delayed transcription termination, but only in a subset of genes. POINT-seq analysis reveals widespread transcriptional readthrough beyond canonical termination sites upon SETD2 loss/mutation, affecting 15–24% of genes. We demonstrate that defective termination following SETD2 loss/mutation is driven by a combination of increased cryptic transcription initiation and impaired 3′ pre-mRNA cleavage. In contrast, genes that maintain proper termination show significant downregulation. Additionally, we find that SETD2 ensures proper termination independently of alternative polyadenylation, underscoring the distinction between transcription termination and 3′ end processing. Our findings highlight that methyltransferase activity of SETD2 is a crucial regulator of transcriptional integrity, preventing cryptic initiation and promoting efficient 3′ end processing
2026-02-09 | GSE301037 | GEO
Project description:SETD2 is a key histone methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity has been implicated in various cancers, including renal cell carcinoma (RCC). In RCC, SETD2 mutations have been linked to defects in transcription termination, though the underlying mechanism remains unclear. Here, using nascent transcriptomics in SETD2 knockouts and RCC patient-derived cells, we show that SETD2 loss leads to delayed transcription termination, but only in a subset of genes. POINT-seq analysis reveals widespread transcriptional readthrough beyond canonical termination sites upon SETD2 loss/mutation, affecting 15–24% of genes. We demonstrate that defective termination following SETD2 loss/mutation is driven by a combination of increased cryptic transcription initiation and impaired 3′ pre-mRNA cleavage. In contrast, genes that maintain proper termination show significant downregulation. Additionally, we find that SETD2 ensures proper termination independently of alternative polyadenylation, underscoring the distinction between transcription termination and 3′ end processing. Our findings highlight that methyltransferase activity of SETD2 is a crucial regulator of transcriptional integrity, preventing cryptic initiation and promoting efficient 3′ end processing
2026-02-09 | GSE301036 | GEO
Project description:SETD2 is a key histone methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity has been implicated in various cancers, including renal cell carcinoma (RCC). In RCC, SETD2 mutations have been linked to defects in transcription termination, though the underlying mechanism remains unclear. Here, using nascent transcriptomics in SETD2 knockouts and RCC patient-derived cells, we show that SETD2 loss leads to delayed transcription termination, but only in a subset of genes. POINT-seq analysis reveals widespread transcriptional readthrough beyond canonical termination sites upon SETD2 loss/mutation, affecting 15–24% of genes. We demonstrate that defective termination following SETD2 loss/mutation is driven by a combination of increased cryptic transcription initiation and impaired 3′ pre-mRNA cleavage. In contrast, genes that maintain proper termination show significant downregulation. Additionally, we find that SETD2 ensures proper termination independently of alternative polyadenylation, underscoring the distinction between transcription termination and 3′ end processing. Our findings highlight that methyltransferase activity of SETD2 is a crucial regulator of transcriptional integrity, preventing cryptic initiation and promoting efficient 3′ end processing
2026-02-09 | GSE301041 | GEO
Project description:SETD2 is a key histone methyltransferase responsible for depositing histone H3 lysine 36 trimethylation (H3K36me3). Loss of its enzymatic activity has been implicated in various cancers, including renal cell carcinoma (RCC). In RCC, SETD2 mutations have been linked to defects in transcription termination, though the underlying mechanism remains unclear. Here, using nascent transcriptomics in SETD2 knockouts and RCC patient-derived cells, we show that SETD2 loss leads to delayed transcription termination, but only in a subset of genes. POINT-seq analysis reveals widespread transcriptional readthrough beyond canonical termination sites upon SETD2 loss/mutation, affecting 15–24% of genes. We demonstrate that defective termination following SETD2 loss/mutation is driven by a combination of increased cryptic transcription initiation and impaired 3′ pre-mRNA cleavage. In contrast, genes that maintain proper termination show significant downregulation. Additionally, we find that SETD2 ensures proper termination independently of alternative polyadenylation, underscoring the distinction between transcription termination and 3′ end processing. Our findings highlight that methyltransferase activity of SETD2 is a crucial regulator of transcriptional integrity, preventing cryptic initiation and promoting efficient 3′ end processing
2026-02-09 | GSE301207 | GEO