Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA381790 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5419960.fastq.gz | Fastqsanger.gz | |||
| SRR5419970.fastq.gz | Fastqsanger.gz | |||
| SRR5419980.fastq.gz | Fastqsanger.gz | |||
| SRR5419961.fastq.gz | Fastqsanger.gz | |||
| SRR5419971.fastq.gz | Fastqsanger.gz |
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Project description:Dysregulation of kinase signaling pathways via mutations favors tumor cell survival and resistance to therapy and it is common in cancer. Here, we reveal a novel mechanism of post-translational regulation of kinase signaling and nuclear receptor activity via deubiquitination in acute leukemia. We observed that the ubiquitin specific protease 11 (USP11) is highly expressed in lymphoblastic leukemia and associates with poor prognosis in this disease. USP11 ablation inhibits leukemia growth in vitro and in vivo, sparing normal hematopoiesis and thymus development, suggesting that USP11 could be a therapeutic target in leukemia. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK). Deubiquitination of LCK controls its activity, thereby altering T cell receptor signaling. Impairment of LCK activity leads to increased expression of the glucocorticoid receptor transcript, culminating into transcriptional activation of pro-apoptotic target genes, and sensitizes cells to glucocorticoids in primary T cell leukemia patient samples. The transcriptional activation of pro-apoptotic target genes, such as BCL2L11, is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Pharmacological inhibition of USP7 or genetic knockout of USP7 in combination treatment of glucocorticoid displayed improved anti-T-ALL efficacy in vivo. Our data unveil how dysregulated deubiquitination controls signaling pathways, leading to cancer cell survival and drug non-response, and suggest novel therapeutic combinations towards targeting leukemia.
2022-02-28 | MSV000088930 | MassIVE
Project description:Transcriptional deregulation plays a major role in acute myeloid leukemia, identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence showing the functional involvement and therapeutic potentials of targeting PRMT1 with H4R3 methyltransferase activity in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C with H3K9 demethylase activity by chimeric transcription factors to mediate epigenetic reprogramming. Inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a novel and targetable epigenetic circuitry mediated by PRMT1 and KDM4C in acute leukemia.
2016-01-14 | E-MTAB-3322 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we chemically inhibited the deubiquinating enzyme USP7 and assayed for gene expression changes. This piece of data was further integrated to epigenetic changes using ChIP-Sequencing analysis of H3K27me3, H2AUb, H2BUb, H3K27Ac and H3K79me2 upon inhibition of USP7. These results coupled helped to determine the role of USP7 in stabilizing and promoting T-ALL leukemia. We also compared the gene expression and epigenetic changes of USP7 inhibition with inhibition of NOTCH1 pathway and JMJD3.
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Project description:Cancer arises from the malignant interplay between oncogenic signaling and cell specification. Transcriptionally activated stem, growth and survival programs reshape an epigenomic identity defined by a transcriptional core regulatory circuitry. To study and disrupt oncogenic transcription, we first created inhibitors of BET bromodomains. Selective antagonism of oncogenic transcriptional signaling arises from bromodomain-specific activity. Recently, we innovated a strategy to induce selective and pronounced degradation of BET coactivator proteins via phthalimide conjugation for E3 ubiquitin ligase recruitment. Degraders of BET bromdomains (dBETs) exhibited superior efficacy to bromodomain inhibitors in cultivated leukemia cells, through unknown mechanisms. Here, we use chemically optimized small-molecule degronimids and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in the control of global productive transcriptional elongation. Rapid loss of BRD4 attenuates phosphorylation of the carboxy-terminal domain of RNA polymerase II, independent of genomewide recruitment of CDK9 to promoters, leading to a collapse of the transcriptional core regulatory circuitry. These mechanistic studies are performed in translational models of T-cell acute lymphoblastic leukemia, a disease emblematic for transcriptional addiction, to establish a rationale for human clinical investigation. RNA-Seq for DMSO, dBET6, or JQ1 treated MOLT4 cells
2016-04-01 | E-GEOD-79253 | biostudies-arrayexpress
Project description:Modification by ubiquitin controls the stability of most cellular proteins, and deregulation contributes to a variety of human diseases such as cancer. Deubiquitinases (DUBs) remove ubiquitin from proteins, and the inhibition of DUBs has been recognized as a therapeutic strategy to induce degradation of specific proteins, a concept extendable to ‘undruggable’ targets such as transcription factors. However, this potential has remained untapped; specific small molecule inhibitors for DUBs are scarce and insights into mechanisms of action are limited. Ubiquitin specific protease (USP) 7 stabilises the oncogenic E3 ligase MDM2 that destabilises the tumour suppressor p53 and inhibition of USP7 results in MDM2 degradation and p53 re-activation in a variety of cancers. We here present two small molecule inhibitors, FT671 and FT827, that inhibit USP7 with nanomolar affinity and display exquisite specificity towards USP7 in vitro and in cells. USP7-inhibitor co-crystal structures reveal that both compounds target the auto-inhibited apo-form of USP7 and bind in proximity to the misaligned catalytic triad in a dynamic hydrophobic pocket that serves as the binding site for the ubiquitin C-terminus. The unique auto-inhibited conformation of apo USP7 differs from other USP DUBs, explaining compound selectivity. Consistent with USP7 target engagement in cells, FT671 destabilises MDM2, stabilises p53 and results in transcription of p53 target genes, induction of the tumour suppressor p21, and tumour growth inhibition in vivo.
2018-04-05 | PXD006418 | Pride
Project description:Search for a novel therapeutic target in myeloid leukemia
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Project description:Background: The oncogenic protein HOXA9 plays a critical role in leukemia transformation and maintenance, and its aberrant expression is a hallmark of most aggressive acute leukemia. Although inhibiting the upstream regulators of HOXA9 has been proven as a significant therapeutic intervention, the comprehensive regulation network controlling HOXA9 expression in leukemia has not been systematically investigated. Results: Here, we perform genome-wide CRISPR/Cas9 screening in the HOXA9-driven reporter acute leukemia cells. We identify a poorly characterized RNA-binding protein, RBM5, as the top candidate gene required to maintain leukemia cell fitness. RBM5 is highly overexpressed in acute myeloid leukemia (AML) patients compared to healthy individuals. RBM5 loss triggered by CRISPR knockout and shRNA knockdown significantly impairs leukemia maintenance in vitro and in vivo. Through domain CRISPR screening, we reveal that RBM5 functions through a noncanonical transcriptional regulation circuitry rather than RNA splicing, such an effect depending on DNA-binding domains. By integrative analysis and functional assays, we identify HOXA9 as the downstream target of RBM5. Ectopic expression of HOXA9 rescues impaired leukemia cell proliferation upon RBM5 loss. Importantly, acute protein degradation of RBM5 through auxin-inducible degron system immediately reduces HOXA9 transcription. Conclusions: We identify RBM5 as a new upstream regulator of HOXA9 and reveal its essential role in controlling the survival of AML. These functional and molecular mechanisms further support RBM5 as a promising therapeutic target for myeloid leukemia treatment. Keywords: Acute myeloid leukemia; CRISPR screen; Genome editing; HOXA9; RBM5.
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Project description:A transcriptional cascade as therapeutic target for malaria controls
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Project description:Cancer arises from the malignant interplay between oncogenic signaling and cell specification. Transcriptionally activated stem, growth and survival programs reshape an epigenomic identity defined by a transcriptional core regulatory circuitry. To study and disrupt oncogenic transcription, we first created inhibitors of BET bromodomains. Selective antagonism of oncogenic transcriptional signaling arises from bromodomain-specific activity. Recently, we innovated a strategy to induce selective and pronounced degradation of BET coactivator proteins via phthalimide conjugation for E3 ubiquitin ligase recruitment. Degraders of BET bromdomains (dBETs) exhibited superior efficacy to bromodomain inhibitors in cultivated leukemia cells, through unknown mechanisms. Here, we use chemically optimized small-molecule degronimids and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in the control of global productive transcriptional elongation. Rapid loss of BRD4 attenuates phosphorylation of the carboxy-terminal domain of RNA polymerase II, independent of genomewide recruitment of CDK9 to promoters, leading to a collapse of the transcriptional core regulatory circuitry. These mechanistic studies are performed in translational models of T-cell acute lymphoblastic leukemia, a disease emblematic for transcriptional addiction, to establish a rationale for human clinical investigation.
2017-09-18 | GSE79288 | GEO
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