A5060375783- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Acute Myeloid Leukemia Research
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- CRISPR and Genetic Engineering
- Receptor Mechanisms and Signaling
- Neuroendocrine Tumor Research Advances
- Lung Cancer Research Studies
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Acute Lymphoblastic Leukemia research
- Genetics and Neurodevelopmental Disorders
- Single-cell and spatial transcriptomics
- Genetic Syndromes and Imprinting
- Radiopharmaceutical Chemistry and Applications
- Viral Infectious Diseases and Gene Expression in Insects
- Glioma Diagnosis and Treatment
- Virus-based gene therapy research
- Chromatin Remodeling and Cancer
Children's Cancer Institute Australia
2019-2025
UNSW Sydney
2019-2025
Cancer Institute of New South Wales
2021-2024
Peter MacCallum Cancer Centre
2023-2024
The University of Melbourne
2023-2024
Abstract To achieve the very high oncoprotein levels required to drive malignant state cancer cells utilise ubiquitin proteasome system upregulate transcription factor levels. Here our analyses identify ALYREF , expressed from most common genetic copy number variation in neuroblastoma, chromosome 17q21-ter gain as a key regulator of MYCN protein turnover. We show strong co-operativity between and transgenic models neuroblastoma vitro vivo. The two proteins form nuclear coactivator complex...
Abstract The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely because the inability current therapies to kill stem cells (LSCs) with intrinsic resistance. Loss stress sensor growth arrest and DNA damage-inducible 45 alpha (GADD45A) is implicated in poor clinical outcomes, but its role LSCs AML pathogenesis unknown. Here, we define GADD45A as a key downstream target G protein-coupled receptor (LGR)4 pathway discover regulatory for loss promoting leukemia-initiating...
Peripheral neuroblastic tumors (PNTs) represent a spectrum of neural-crest-derived tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Malignant cells in PNTs are theorized to interconvert between adrenergic/noradrenergic mesenchymal/neural crest cell states. Here, single-cell RNA-sequencing analysis 10 demonstrates extensive transcriptomic heterogeneity. Trajectory modeling suggests that malignant neuroblasts move adrenergic mesenchymal states via an intermediate...
Abstract Background Bivalent chromatin is an exemplar of epigenetic plasticity. This co-occurrence active-associated H3K4me3 and inactive-associated H3K27me3 histone modifications on opposite tails the same nucleosome occurs predominantly at promoters that are poised for future transcriptional upregulation or terminal silencing. We know little dynamics, resolution, regulation this state outside embryonic stem cells where it was first described. partly due to technical challenges...
Abstract Tumorigenic drivers of MYCN gene nonamplified neuroblastoma remain largely uncharacterized. Long noncoding RNAs (lncRNAs) regulate tumorigenesis, however, there is little literature on therapeutic targeting lncRNAs with small molecule compounds. Here PRKCQ‐AS1 identified as the lncRNA most overexpressed in nonamplified, compared ‐amplified, cell lines. expression controlled by super‐enhancers, and RNA bound to MSI2 protein. immunoprecipitation sequencing BMX mRNA transcript...
Abstract Background: While MYCN-amplified neuroblastoma has been the focus of research in past three decades, most human neuroblastomas do not harbour MYCN oncogene amplification, and their tumorigenic factors are unknown. Long non-coding RNAs (lncRNAs) regulate tumorigenesis by modulating expression molecular targets, however, there is limited literature on therapeutic targeting lncRNAs with small molecule compounds. Aims: To determine oncogenic mechanism though which lncRNA lncNB promotes...
Embryonic regulators are often re-expressed in cancers, however the functional and molecular significance of this is not always understood. The epigenetic priming factors Developmental Pluripotency Associated 2 4 (DPPA2/4) have crucial roles early development implicated cancer pathogenesis. We reveal non-small cell lung (NSCLC), DPPA2/4 co-expression associated with poorly differentiated tumours, impaired patient outcomes accelerated vivo xenograft tumour growth. Proteomic analyses dimerise...
MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced protein stability key component oncogenesis and maintained by multiple feedforward expression loops involving transactivation target genes. Here, we reveal oncogenic role novel binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that occupies PA2G4 gene promoter, stimulating transcription. Direct to blocked...
Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but insufficient to drive leukemogenesis. Here we show that SPI1 fusions combination with activating NRAS mutations an immature T-ALL vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic mutation also results higher leukemic stem cell frequency. Mechanistically, genetic deletion β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1...
Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, much more combination with other anti-cancer agents. To identify novel compounds which act synergistically inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed cell-based, high-throughput drug screen 10,560 small molecule from drug-like diversity library and identified compound (SE486-11) enhanced cytotoxic effects...
Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% acute leukemias and characteristically define disease with poor outcome. Driven by unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that novel anti-cancer agent, curaxin CBL0137, induces decondensation chromatin cancer cells, delays leukemia progression potentiates standard care chemotherapies preclinical models. Based on promising potential histone...
Many of the pro-tumorigenic functions oncogene MYCN are attributed to its regulation global gene expression programs. Alternative splicing is another important regulator and has been implicated in neuroblastoma development, however, molecular mechanisms remain unknown. We found that up-regulated core spliceosomal protein, SNRPD3, models initiation progression. High mRNA SNRPD3 human tissues was a strong, independent prognostic factor for poor patient outcome. Repression correlated with loss...
The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used treat cancer. Neuroblastoma common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression the adenine nucleotide translocase 2 (SLC25A5/ANT2), was strong predictor patient prognosis...
Changes in the epigenetic landscape are a hallmark of aging that contributes to irreversible decline organismal fitness ultimately leading aging-related diseases.Epigenetic modifications regulate cellular memory processes genomic imprinting and X-chromosome inactivation (XCI) ensure monoallelic expression imprinted X-linked genes.Whether aging-associated changes affect maintenance XCI has not been comprehensively studied.Here, we investigate allele-specific transcriptional signatures brain,...
Abstract Background The child cancer, neuroblastoma (NB), is characterised by a low incidence of mutations and strong oncogenic embryonal driver signals. Many new targeted epigenetic modifier drugs have failed in human trials as monotherapy. Methods We performed high‐throughput, combination chromatin‐modifier drug screen against NB cells. screened 13 candidates 78 unique combinations. Results found that the two histone methyltransferase (HMT) inhibitors: GSK343, targeting EZH2, SGC0946,...
Abstract Peripheral neuroblastic tumors (PNTs) are the most common extracranial solid in early childhood. They represent a spectrum of neural crest derived including neuroblastoma, ganglioneuroblastoma and ganglioneuroma. PNTs exhibit heterogeneity due to interconverting malignant cell states described as adrenergic/nor-adrenergic or mesenchymal/neural origin. The factors determining individual patient levels tumor heterogeneity, their impact on phenotype, presence other unknown. Here,...
Abstract Epigenetic drift is a hallmark of aging that contributes to the irreversible decline in organismal fitness ultimately leading aging-related diseases. modifications regulate cellular memory epigenetic processes genomic imprinting and X-chromosome inactivation ensure monoallelic expression imprinted X-linked genes. Whether affects maintenance has not been comprehensively studied. Here, we investigate allele-specific transcriptional signatures brain, by comparing juvenile old hybrid...
Abstract Background Bivalent chromatin is an exemplar of epigenetic plasticity. This co-occurrence active-associated H3K4me3 and inactive-associated H3K27me3 histone modifications on opposite tails the same nucleosome occurs predominantly at promoters where it poises them for future transcriptional upregulation or terminal silencing. We know little dynamics, resolution, regulation this state outside embryonic stem cells was first described. partly due to technical challenges distinguishing...
This is a detailed protocol for performing sequential ChIP-reChIP to map H3K4me3-H3K27me3 bivalent chromatin regions. It has been optimised using mouse embryonic stem cells and so may need be refined based on your cell type of interest. For more details please refer the accompanying manuscript (Hoet al. 2023).
MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing mutant mouse genomes identified Ring Finger Protein 121 (RNF121
ABSTRACT Changes in gene regulation and expression govern orderly transitions from hematopoietic stem cells to terminally differentiated blood cell types. These are disrupted during leukemic transformation but knowledge of the regulatory changes underpinning this process is elusive. We hypothesised that identifying core networks healthy could provide insights into network alterations perturb state transitions. A heptad transcription factors (LYL1, TAL1, LMO2, FLI1, ERG, GATA2, RUNX1) bind...
<div>Abstract<p>MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability key component oncogenesis and maintained by multiple feedforward expression loops involving transactivation target genes. Here, we reveal oncogenic role novel binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that occupies PA2G4 gene promoter, stimulating...
<div>Abstract<p>MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability key component oncogenesis and maintained by multiple feedforward expression loops involving transactivation target genes. Here, we reveal oncogenic role novel binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that occupies PA2G4 gene promoter, stimulating...