A dual role for PSIP1/LEDGF in T-cell acute lymphoblastic leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1064104 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27506300_1.fastq.gz | Fastqsanger.gz | |||
| SRR27506300_2.fastq.gz | Fastqsanger.gz | |||
| SRR27506500.fastq.gz | Fastqsanger.gz | |||
| SRR27506301_1.fastq.gz | Fastqsanger.gz | |||
| SRR27506301_2.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:A dual role for PSIP1/LEDGF in T-cell acute lymphoblastic leukemia [CUT&RUN]
| PRJNA1064101 | ENA
Project description:A dual role for PSIP1/LEDGF in T-cell acute lymphoblastic leukemia [RNA-seq]
| PRJNA1064102 | ENA
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Although intensified therapeutic protocols have improved the outcome of T-ALL patients, they coincide with severe short- and long-term side effects. In addition, no salvage therapeutic strategies are available for primary therapy-resistant or relapsed T-ALL, resulting in a dismal outcome for these patients. It highlights the need to identify new targets in T-ALL biology that allow the development of less toxic targeted therapies. PSIP1, a histone mark reader, is a dependency factor in KMT2A-rearranged myeloid leukemia, but is dispensable for normal hematopoiesis, making it an attractive therapeutic target. Nonetheless, rare recurrent inactivating mutations and deletions of PSIP1, suggest that PSIP1 could act as a tumor suppressor in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice and we identified a correlation with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several human and murine T-ALL cell lines. In these cell lines, PSIP1 loss leads to a significant downregulation of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and is associated with a reduction in mitochondrial respiration. Similarly to what was observed for PSIP1, loss of COX20 expression also leads to an impairment of proliferation in these T-ALL cell lines. These data corroborate that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
2024-10-20 | GSE253138 | GEO
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Although intensified therapeutic protocols have improved the outcome of T-ALL patients, they coincide with severe short- and long-term side effects. In addition, no salvage therapeutic strategies are available for primary therapy-resistant or relapsed T-ALL, resulting in a dismal outcome for these patients. It highlights the need to identify new targets in T-ALL biology that allow the development of less toxic targeted therapies. PSIP1, a histone mark reader, is a dependency factor in KMT2A-rearranged myeloid leukemia, but is dispensable for normal hematopoiesis, making it an attractive therapeutic target. Nonetheless, rare recurrent inactivating mutations and deletions of PSIP1, suggest that PSIP1 could act as a tumor suppressor in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice and we identified a correlation with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several human and murine T-ALL cell lines. In these cell lines, PSIP1 loss leads to a significant downregulation of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and is associated with a reduction in mitochondrial respiration. Similarly to what was observed for PSIP1, loss of COX20 expression also leads to an impairment of proliferation in these T-ALL cell lines. These data corroborate that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
2024-10-20 | GSE253137 | GEO
Project description:The LEDGF transcript from the PSIP1 gene was knocked down in Jurkat cells using RNAi technology. The resulting Jurkat-derived cell line (Jurkat-siJK2) was compared to a control cell line (wild type Jurkat) using microarray analysis. Genes identified as being modulated by LEDGF were preferential targets of HIV integration. Experiment Overall Design: 2 cell lines were used, Jurkat-siJK2 (experimental) and wild-type Jurkat (control). 3 independent cultures of each cell line were used for independent RNA extractions, labeling reactions and array hybridizations.
2008-06-15 | E-GEOD-7508 | biostudies-arrayexpress
Project description:T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current intensified therapeutic protocols coincide with severe side effects, and no salvage therapy is available for primary therapy-resistant or relapsed patients. This highlights the need to identify new therapeutic targets in T-ALL. PSIP1, dispensable for normal hematopoiesis, is a dependency factor in KMT2A-rearranged myeloid leukemia. Nonetheless, loss-of-function mutations suggest a tumor suppressor role for PSIP1 in T-ALL. Here, we demonstrate that the loss of Psip1 accelerates T-ALL initiation in mice which we correlated with reduced H3K27me3 binding. Contrastingly, loss of PSIP1 impaired cell proliferation in several T-ALL cell lines. In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.
| S-EPMC11529709 | biostudies-literature
Project description:R-loops are transcriptional by-products that pose a persistent threat to genome integrity and are implicated in accelerated ageing and cancer. PSIP1/LEDGF is a multifunctional chromatin protein that associates with transcriptional elongation machinery. Here, we demonstrated that PSIP1 interacts with R-loops generated at the site of transcription and along with the factors involved in R-loop resolution, including PARP1. Reduced PSIP1 levels in human and mouse cells lead to an increase in R-loop levels and DNA damage at the PSIP1 binding sites. This increased R-loops and DNA damage was specific at the RNA polymerase II transcription sites, causing local transcriptional arrest. In addition, we demonstrate that PSIP1 can be targeted for increasing the sensitivity of cancer cells to PARP1 inhibitors and transcription-coupled DNA damaging agents. These findings show the critical role of PSIP1 in reducing the R-loop burden and DNA damage at the transcriptionally active regions of the genome.
2023-12-08 | GSE220233 | GEO
Project description:R-loops are transcriptional by-products that pose a persistent threat to genome integrity and are implicated in accelerated ageing and cancer. PSIP1/LEDGF is a multifunctional chromatin protein that associates with transcriptional elongation machinery. Here, we demonstrated that PSIP1 interacts with R-loops generated at the site of transcription and along with the factors involved in R-loop resolution, including PARP1. Reduced PSIP1 levels in human and mouse cells lead to an increase in R-loop levels and DNA damage at the PSIP1 binding sites. This increased R-loops and DNA damage was specific at the RNA polymerase II transcription sites, causing local transcriptional arrest. In addition, we demonstrate that PSIP1 can be targeted for increasing the sensitivity of cancer cells to PARP1 inhibitors and transcription-coupled DNA damaging agents. These findings show the critical role of PSIP1 in reducing the R-loop burden and DNA damage at the transcriptionally active regions of the genome.
2023-12-08 | GSE220232 | GEO
Project description:R-loops are transcriptional by-products that pose a persistent threat to genome integrity and are implicated in accelerated ageing and cancer. PSIP1/LEDGF is a multifunctional chromatin protein that associates with transcriptional elongation machinery. Here, we demonstrated that PSIP1 interacts with R-loops generated at the site of transcription and along with the factors involved in R-loop resolution, including PARP1. Reduced PSIP1 levels in human and mouse cells lead to an increase in R-loop levels and DNA damage at the PSIP1 binding sites. This increased R-loops and DNA damage was specific at the RNA polymerase II transcription sites, causing local transcriptional arrest. In addition, we demonstrate that PSIP1 can be targeted for increasing the sensitivity of cancer cells to PARP1 inhibitors and transcription-coupled DNA damaging agents. These findings show the critical role of PSIP1 in reducing the R-loop burden and DNA damage at the transcriptionally active regions of the genome.
2023-12-08 | GSE220231 | GEO
Project description:Mixed-lineage leukemia (MLL) represents a genetically distinct and aggressive subset of human acute leukemia carrying chromosomal translocations of the MLL gene. These translocations result in oncogenic fusions that mediate aberrant recruitment of transcription machinery to MLL target genes. The N-terminus of MLL and MLL-fusions form a complex with Lens Epithelium-Derived Growth Factor (LEDGF/p75; encoded by the Psip1 gene) and MENIN. This complex contributes to the association of MLL and MLL-fusion multiprotein complexes with chromatin. Several studies have shown that both MENIN and LEDGF/p75 are required for efficient MLL fusion-mediated transformation and for the expression of downstream MLL-regulated genes like HOXA9 and MEIS1. In light of the development of a therapeutic strategy targeting this complex, understanding the function of LEDGF/p75 in normal hematopoiesis is crucial. We generated a conditional Psip1 knockout mouse model in the hematopoietic compartment and examined the effects of LEDGF/p75 depletion in postnatal hematopoiesis and the initiation of MLL leukemogenesis. Psip1 knockout mice were viable but showed several defects in hematopoiesis, reduced colony-forming activity in vitro, decreased expression of Hox genes in hematopoietic stem cells and decreased MLL occupancy at MLL target genes. Finally, in vitro and in vivo experiments showed that LEDGF/p75 is dispensable for steady state hematopoiesis but essential for the initiation of MLL-mediated leukemia. These data corroborate the MLL-LEDGF/p75 interaction as novel target for the treatment of MLL-rearranged leukemia.
2017-09-30 | GSE104138 | GEO