Role of LEDGF/p75 in MLL chemoresistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA691895 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13428200.fastq.gz | Fastqsanger.gz | |||
| SRR13428201.fastq.gz | Fastqsanger.gz | |||
| SRR13428202.fastq.gz | Fastqsanger.gz | |||
| SRR13428203.fastq.gz | Fastqsanger.gz | |||
| SRR13428196.fastq.gz | Fastqsanger.gz |
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Project description:The study has been focused on the characterization of the role of LEDGF/p75 in chemiresistance in pediatric leukemia Abstract: MLL is an aggressive subtype of leukemia with a poor prognosis that mostly affects pediatric patients. MLL-rearranged fusion proteins (MLLr) induce aberrant target gene expression resulting in leukemogenesis. MLL and its fusions are tethered to chromatin by LEDGF/p75, a transcriptional co-activator that specifically recognizes H3K36me2/3. LEDGF/p75 is ubiquitously expressed and associated with regulation of gene expression, autoimmune responses and HIV replication. LEDGF/p75 was proven to be essential for leukemogenesis in MLL. Apart from MLL, LEDGF/p75 has been linked to lung, breast and prostate cancer. Intriguingly, LEDGF/p75 interacts with Med-1, which co-localizes with BRD4. Both are known as co-activators of super-enhancers. Here, we describe LEDGF/p75-dependent chemoresistance of MLLr cell lines. Investigation of the underlying mechanism revealed a role of LEDGF/p75 in the cell cycle and in survival pathways and showed that LEDGF/p75 protects against apoptosis during chemotherapy. Remarkably, LEDGF/p75 levels also affected expression of BRD4 and Med1. Altogether, our data suggest a role of LEDGF/p75 in cancer survival, stem cell renewal, and activation of nuclear super enhancers.
2021-01-14 | GSE164751 | 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
Project description:Mixed lineage leukemia-rearranged (MLLr) leukemia is a genetically distinct subtype of leukemia driven by a reciprocal chromosomal translocation or partial tandem duplications of internal coding regions of the MLL gene KMT2A. These rearrangements result in in-frame genes, translated to oncogenic fusion proteins deregulating the MLL target genes (e.g. HoxA family, Meis1, Cdk6), promoting leukemogenesis and tumor progression. To regulate gene expression, unstructured N-terminal motifs found in MLL form a ternary complex with menin and the integrase binding domain (IBD) of the p75 splice variant of Lens Epithelium Derived Growth Factor (LEDGF/p75). Formation of the ternary complex is crucial for MLL-r leukemogenesis. Hepatoma derived growth factor related protein 2 (HRP2) is the only human paralog of LEDGF/p75 with identical functional domains. We investigated its role in normal hematopoiesis and leukemia. We demonstrate that adult Hrp2 knockout mice can be distinguished from their wild type littermates by increased neutrophils in the hematopoietic system. Colony formation experiments and Gene Set Enrichment Analysis on lin- HSC hinted towards a stem-like state supported by HRP2. In context of leukemia, we observe a more general role for HRP2 in the survival of leukemic cells independently of MLL.
2020-07-11 | GSE154202 | GEO
Project description:LEDGF/p75 is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis
| PRJNA411792 | ENA
Project description:Role of HRP2 in mixed lineage leukemia compared to its paralog LEDGF/p75
| PRJNA645412 | ENA
Project description:LEDGF/p75 promotes transcriptional pausing through preventing SPT5 phosphorylation
| PRJNA1053782 | ENA
Project description:The LEDGF transcript from the PSIP1 gene was knocked down using RNAi technology. The resulting 293T derived cell line (293TsiLL) was compared to a control cell line (293TsiScram) using microarray analysis. Genes identified as being modulated by LEDGF were preferential targets of HIV integration. Experiment Overall Design: 2 cell lines were used, 293TsiLL (experimental) and 293TsiScram (control). 4 independent cultures of each cell line were used for independent RNA extractions, labeling reactions and array hybridizations.
2007-10-27 | E-GEOD-3485 | biostudies-arrayexpress
Project description:Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in breast cancer initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in breast cancer progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses indicated that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration, and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.
2017-06-06 | GSE99699 | 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 the 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 the 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 such as HOXA9 and MEIS1 In light of developing 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 the 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.
| S-EPMC5755044 | biostudies-literature
Project description:Comparative gene expression profiling of olfactory enshealting cells : p75 High vs p75 Low cells population
2011-07-20 | GSE30797 | GEO