A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-ALL
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA839729 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19310378.fastq.gz | Fastqsanger.gz | |||
| SRR19310379.fastq.gz | Fastqsanger.gz | |||
| SRR19310380.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 3 of 3 |
Similar Datasets
Project description:C57BL6 mice harboring Sirt1 conditional knockout NOTCH1-DE-induced leukemias were treated with vehicle (control) or tamoxifen to induce isogenic deletion of Sirt1. Here we report the H4K12ac ChIP-seq epigenetic profile of leukemic blasts obtained from the spleen from control- or tamoxifen-treated leukemic mice.
2022-12-08 | GSE203386 | GEO
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1-SIRT1-KAT7 link as a therapeutic vulnerability in T-ALL, in which the histone deacetylase SIRT1 is overexpressed downstream of a NOTCH1-bound enhancer. SIRT1 loss impaired leukemia generation, whereas SIRT1 overexpression accelerated leukemia and conferred resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, pharmacologic or genetic inhibition of SIRT1 resulted in significant antileukemic effects. Global acetyl proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene-expression profiling revealed metabolic changes together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a nonacetylatable KAT7-mutant partly rescued SIRT1 loss-induced proliferation defects. Overall, our results uncover therapeutic targets in T-ALL and reveal a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.SignificanceWe identify a T-ALL axis whereby NOTCH1 activates SIRT1 through an enhancer region, and SIRT1 deacetylates and activates KAT7. Targeting SIRT1 shows antileukemic effects, partly mediated by KAT7 inactivation. Our results reveal T-ALL therapeutic targets and uncover a rheostat mechanism between deacetylase/acetyltransferase activities with potentially broader cancer relevance. This article is highlighted in the In This Issue feature, p. 1.
| S-EPMC9818047 | biostudies-literature
Project description:C57BL6 mice harboring Sirt1 conditional knockout NOTCH1-HDDPEST-induced leukemias were treated with vehicle (control) or tamoxifen to induce isogenic deletion of Sirt1. Here we report the gene expression profile of leukemic blasts obtained from the spleen from control- or tamoxifen-treated leukemic mice.
2024-01-01 | GSE192842 | GEO
Project description:C57BL6 mice harboring Sirt1 conditional knockout NOTCH1-DE-induced leukemias were treated with vehicle (control) or tamoxifen to induce isogenic deletion of Sirt1. Here we report the gene expression profile of leukemic blasts obtained from the spleen from control- or tamoxifen-treated leukemic mice.
2022-12-08 | GSE203387 | GEO
Project description:In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary to this model, we show that the histone acetyltransferase KAT7 (HBO1/MYST2) is required genome-wide for histone H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, we found that KAT7 and H3K14ac were present not only at transcribed genes, but also at inactive genes, intergenic regions and in heterochromatin. KAT7 and H3K14ac were not required for the continued transcription of genes that were actively transcribed at the time of loss of KAT7, but indispensable for the activation of repressed genes. The absence of KAT7 abrogated neural stem cell plasticity, diverse differentiation pathways and cerebral cortex development. Reexpression of KAT7 restored stem cell developmental potential. Overexpression of KAT7 enhanced neuron and oligodendrocyte differentiation. Our data suggest that KAT7 prepares chromatin for transcriptional activation and is a prerequisite for gene activation.
2022-12-09 | GSE220602 | GEO
Project description:Histone acetyltransferases (HATs) play a crucial role in transcriptional regulation by acetylating histones. Dysregulation of HAT activity is implicated in developmental disorders and cancer. In this study, we discovered an upregulated KAT7 signaling pathway in colorectal cancer (CRC) and its association with poor patient survival. Knockdown of KAT7 suppressed CRC cell viability, proliferation, migration, and invasion while promoting apoptosis. Conversely, KAT7 overexpression enhanced these cellular processes. In vivo experiments demonstrated that KAT7 knockdown inhibited CRC growth and lung metastasis. Mechanistically, KAT7 acetylated histone H3 at lysine 14 (H3K14) to enhance MRAS transcription, which activated the MAPK/ERK pathway and promoted tumorigenesis. Overexpression of MRAS or treatment with the ERK activator C6 Ceramide rescued the tumor inhibition caused by KAT7 silencing. The acetyltransferase activity of KAT7 is essential for CRC progression. Reexpression of KAT7, but not KAT7 acetyltransferase activity-deficient mutants, rescued MRAS expression, ERK phosphorylation, and CRC tumorigenesis in KAT7 knockdown CRC cells. Taken together, our results define the essential role of KAT7 in CRC tumorigenesis, rationalizing its potential as a therapeutic target for CRC treatment.
2024-06-27 | GSE270298 | GEO
Project description:Understanding the genetic and epigenetic bases of cellular senescence is instrumental to aging intervention. We performed genome-wide CRISPR/Cas9-based screens in two human mesenchymal precursor cell (hMPC) models of progeroid syndromes and identified hundreds of genes whose deficiency alleviated cellular senescence. Among them, KAT7, a histone acetyltransferase, ranked as a top hit in both models. Inactivation of KAT7 decreased H3 lysine 14 acetylation (H3K14ac), repressed p15INK4b transcription, and rejuvenated both physiologically and pathologically aged cells. Moreover, lentiviral vectors encoding Cas9/sg-Kat7 alleviated liver senescence and extended healthspan and lifespan of mice. Our findings demonstrate that CRISPR/Cas9-based genetic screening is a robust method for systematically uncovering unknown senescence genes, of which KAT7 may represent a new therapeutic target for aging intervention.
2020-10-09 | GSE124197 | GEO
Project description:Genome sequencing is revealing a vast mutational landscape in leukemia, offering new opportunities for treatment with targeted therapy. Here, we identify two patients with acute myelogenous leukemia and B-cell acute lymphoblastic leukemia whose tumors harbor point mutations in the ALK kinase. The mutations reside in the extracellular domain of ALK and are potently transforming in cytokine-independent cellular assays and primary mouse bone marrow colony formation studies. Strikingly, both mutations conferred sensitivity to ALK kinase inhibitors, including the FDA-approved drug crizotinib. On the basis of our results, we propose that tumors harboring ALK mutations may be therapeutically tractable for personalized treatment of certain aggressive leukemias with ALK inhibitors.
| S-EPMC4453002 | biostudies-literature
Project description:Alveolar Soft Part Sarcoma is driven by ASPSCR1::TFE3-dependent and therapeutically targetable transcriptional programs [RNA-Seq]
| PRJNA987537 | ENA
Project description:Alveolar Soft Part Sarcoma is driven by ASPSCR1::TFE3-dependent and therapeutically targetable transcriptional programs [ATAC-Seq]
| PRJNA1077312 | ENA