Similar Datasets
Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
2022-08-22 | GSE181189 | GEO
Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
2022-08-22 | GSE181188 | GEO
Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
2022-08-22 | GSE181186 | GEO
Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
2022-07-01 | GSE181187 | GEO
Project description:Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. We took advantage of the PLZF/RARA retinoic acid (RA) resistant acute promyelocytic leukemia (APL) model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. Combining epigenomic profiling with mouse-derived models for Ezh2 catalytic inhibition or total KO, we revealed an independent methyltransferase Ezh2 activity linked to RA resistance. These findings demonstrate the power of single-cell multi-omics integration to highlight paths to sensitize therapy-resistant leukemia cells
2022-08-22 | GSE206345 | GEO
Project description:Single cell analyses reveals a non-canonical EZH2 activity as main driver of RA resistance in PLZF/RARA leukemia [RNA-seq]
| PRJNA751032 | ENA
Project description:The transcription factor PLZF (promyelocytic leukemia zinc finger protein) acts as an epigenetic regulator balancing self-renewal and differentiation of hematopoietic cells through binding to various chromatin-modifying factors. First described as a transcriptional repressor, PLZF is also associated with active transcription, although the molecular bases underlying the differences are unknown. Here, we reveal that in a hematopoietic cell line, PLZF is predominantly associated with transcribed genes. Additionally, we identify a new association between PLZF and the histone methyltransferase, EZH2 at the genomic level. We find that co-occupancy of PLZF and EZH2 on chromatin at PLZF target genes is not associated with SUZ12 or trimethylated lysine 27 of histone H3 (H3K27me3) but with the active histone mark H3K4me3 and active transcription. Removal of EZH2 leads to an increase of PLZF binding and increased gene expression. Our results suggest a new role of EZH2 in restricting PLZF positive transcriptional activity independently of its canonical PRC2 activity.
| S-EPMC5909434 | biostudies-literature
Project description:PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the PLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying PLZF-mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with Plzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by Plzf and PLZF-RARA, in the aberrant self-renewal. Indeed, PLZF-RARA as well as Plzf rendered those cells immortalized through upregulation of Eya2. Eya2 also led to immortalization without differentiation block, while depletion of Eya2 suppressed clonogenicity in cells immortalized by PLZF-RARA without influence on differentiation and apoptosis. Interestingly, cancer outlier profile analysis of human samples of acute myeloid leukemia (AML) in The Cancer Genome Atlas (TCGA) revealed a subtype of AML that strongly expressed EYA2 In addition, gene set enrichment analysis of human AML samples, including TCGA data, showed that this subtype of AML was more closely associated with the properties of leukemic stem cells in its gene expression signature than other AMLs. Therefore, EYA2 may be a target for molecular therapy in this subtype of AML, including PLZF-RARA APL.
| S-EPMC5472835 | biostudies-literature
Project description:The PLZF/RARA fusion protein generated by the t(11;17)(q23;q21) translocation in acute promyelocytic leukaemia (APL) is believed to act as an oncogenic transcriptional regulator recruiting epigenetic factors to genes important for its transforming potential. However, molecular mechanisms associated with PLZF/RARA-dependent leukaemogenesis still remain unclear.We searched for specific PLZF/RARA target genes by ChIP-on-chip in the haematopoietic cell line U937 conditionally expressing PLZF/RARA. By comparing bound regions found in U937 cells expressing endogenous PLZF with PLZF/RARA-induced U937 cells, we isolated specific PLZF/RARA target gene promoters. We next analysed gene expression profiles of our identified target genes in PLZF/RARA APL patients and analysed DNA sequences and epigenetic modification at PLZF/RARA binding sites. We identify 413 specific PLZF/RARA target genes including a number encoding transcription factors involved in the regulation of haematopoiesis. Among these genes, 22 were significantly down regulated in primary PLZF/RARA APL cells. In addition, repressed PLZF/RARA target genes were associated with increased levels of H3K27me3 and decreased levels of H3K9K14ac. Finally, sequence analysis of PLZF/RARA bound sequences reveals the presence of both consensus and degenerated RAREs as well as enrichment for tissue-specific transcription factor motifs, highlighting the complexity of targeting fusion protein to chromatin. Our study suggests that PLZF/RARA directly targets genes important for haematopoietic development and supports the notion that PLZF/RARA acts mainly as an epigenetic regulator of its direct target genes.
| S-EPMC3176768 | biostudies-literature
Project description:The transcription factor PLZF (promyelocytic leukemia zinc finger protein) acts as an epigenetic regulator balancing self-renewal and differentiation of hematopoietic cells through binding to various chromatin-modifying factors. First described as a transcriptional repressor, PLZF is also associated with active transcription, although the molecular bases underlying the differences are unknown. Here, we reveal that, in a hematopoietic cell line, PLZF is predominantly associated with transcribed genes. Additionally, we identify a new association between PLZF and the histone methyltransferase, EZH2 at the genomic level. We find that co-occupancy of PLZF and EZH2 on chromatin at PLZF target genes is not associated with SUZ12 or trimethylated lysine 27 of histone H3 (H3K27me3) but with the active histone mark H3K4me3 and active transcription. Removal of EZH2 leads to an increase of PLZF binding and increased in gene expression. Our results suggest a new role of EZH2 in restricting PLZF positive transcriptional activity independently of its canonical PRC2 activity.
2018-01-26 | GSE109619 | GEO