A5030546478- Acute Myeloid Leukemia Research
- Immune cells in cancer
- Cytokine Signaling Pathways and Interactions
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- RNA modifications and cancer
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Advanced Breast Cancer Therapies
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- Cancer-related Molecular Pathways
- Single-cell and spatial transcriptomics
- Multiple Myeloma Research and Treatments
- Lymphoma Diagnosis and Treatment
- Amino Acid Enzymes and Metabolism
- RNA and protein synthesis mechanisms
- Cancer, Lipids, and Metabolism
- Peptidase Inhibition and Analysis
- Plant biochemistry and biosynthesis
- Glycosylation and Glycoproteins Research
The University of Melbourne
2020-2025
Peter MacCallum Cancer Centre
2017-2025
University of Copenhagen
2024-2025
Expression Génétique Microbienne
2024
To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic transcriptomic analyses following acute inhibition major cellular lysine acetyltransferases P300 CBP in hematological malignancies. We found that catalytic P300/CBP dynamically perturbs steady-state kinetics suppresses oncogenic networks the absence changes to accessibility. CRISPR-Cas9 screening identified NCOR1 HDAC3 co-repressors as principal antagonists...
CDK12 and CDK13 regulate POLII elongation rate processivity influence the selection of transcription termination sites.
Abstract Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor–positive breast cancer currently under evaluation across hundreds clinical trials other types. The success these is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents less understood. Using integrated epigenomic, transcriptomic, proteomic analyses, we demonstrated a novel action CDK4/6 in...
Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR cells solid tumors is limited by tumor-induced immunosuppression, development combination approaches, such as adjuvant programmed death 1 (PD-1) blockade. Current FDA-approved methods for generating utilize either anti-CD3 interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a product...
A new technology, SUGAR-seq, enables simultaneous detection of surface glycans, epitopes, transcripts, and TCR repertoire.
Abstract Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% all acute myeloid leukemias (AML). Limited clinical efficacy FLT3 inhibitors highlights need for alternative therapeutic modalities this subset disease. Using human and murine models FLT3-ITD–driven AML, we demonstrate that FLT3-ITD promotes serine synthesis uptake via ATF4-dependent transcriptional regulation genes de novo biosynthesis pathway neutral amino acid transport. Genetic or...
Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through histone deacetylases (HDAC). models acute myeloid leukemia (AML), differentiation mediated by the HDAC inhibitor (HDACi) panobinostat required activation type I interferon (IFN) pathway. Plasmacytoid dendritic cells...
Abstract The Eμ- Myc mouse is an extensively used model of MYC driven malignancy; however to date there has only been partial characterization co-operative mutations leading spontaneous lymphomagenesis. Here we sequence spontaneously arising lymphomas define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive in the PRC1-like component BCL6-corepressor gene Bcor . Moreover, find unexpected concomitant multigenic lesions involving Cdkn2a loss...
Diffuse large B-cell lymphoma (DLBCL) refers to an aggressive that arises from germinal center (GC) B-cells, which differentiate into plasma cells (PC) produce high affinity antibodies. 40% of DLBCL patients relapse or are refractory the conventional immunochemotherapy treatment, usually with fatal consequences. Therefore, there is unmet critical need find more targeted therapies for DLBCL. characterized by profound alterations in epigenome, correlated poor survival. While epigenetic used as...
The transcription cycle is regulated by dynamic changes in RNA polymerase II (RNAPII) C-terminal domain (CTD) phosphorylation, which are crucial for gene expression. However, the mechanisms regulating transcription-specific cyclin-dependent kinases (CDKs) during remain poorly understood. Here, we show that human CDK12 co-phosphorylates CTD Serine2 and Serine5. This di-phosphorylated Serine2-Serine5 mark may then act as a precursor mono-phosphorylated through Serine5 de-phosphorylation....
High-throughput methodologies are the cornerstone of screening approaches to identify novel compounds that regulate immune cell function. To targeted therapeutics treat disorders and haematological malignancies, there is a need integrate functional cellular information with molecular mechanisms changes in phenotype. We facilitate this goal by combining quantitative methods for dissecting complex simultaneous phenotypic effects genomic analysis. This combination strategy we term Multiplexed...
Abstract The mechanisms ensuring temporally correct, site-specific phosphorylation of the RNA polymerase II C-terminal domain (CTD) by cyclin-dependent kinases (CDKs) during transcription cycle remain poorly understood. Here, we present results from in vitro reconstitution CTD combined with vivo evidence to show that human CDK12 and CDK9 both co-phosphorylate Serine 5 2. However, only is stimulated association elongation-specific factor PAF1C, which CDC73 subunit contains a short, conserved...
JQ1 is a BET-bromodomain inhibitor that has immunomodulatory effects. However, the precise molecular mechanism targets to elicit changes in antibody production not understood. Our results show induces apoptosis, reduces cell proliferation, and as consequence, inhibits antibody-secreting differentiation. ChIP-sequencing reveals selective displacement of Brd4 response acute treatment (<2 h), resulting specific transcriptional repression. After 8 h, subsequent alterations gene expression arise...
ABSTRACT Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit, particularly against hematological malignancies. While these agents affect tumor cell growth and proliferation, recent studies demonstrated that pharmacological de-regulation modifiers may additionally mediate anti-tumor immune responses. Here we discovered a novel mechanism regulation through the histone deacetylases (HDACs). In genetically engineered model t(8;21) AML, leukemia differentiation benefit...
Interferon gamma (IFNγ) is a pro-inflammatory cytokine that directly activates the JAK/STAT pathway. However, temporal dynamics of chromatin remodeling and transcriptional activation initiated by IFNγ have not been systematically profiled in an unbiased manner. Herein, we integrated transcriptomic epigenomic profiling to characterize acute epigenetic changes induced stimulation murine breast cancer model.We identified de novo cis-regulatory elements bound Irf1 were characterized increased...
SUMMARY Gene expression is tightly controlled by Cyclin-dependent kinases (CDKs) which regulate the RNA Polymerase II (RNAPII) transcription cycle at discrete checkpoints. RNAPII pausing a CDK9-controlled rate-limiting process that occurs shortly after initiation and required for spatio-temporal control of in multicellular organisms. We discovered CDK9-mediated pause-release functionally opposed protein phosphatase 2A (PP2A) complex. PP2A dynamically competes key CDK9 substrates, DSIF...
Therapeutic targeting of dysregulated transcription has emerged as a promising strategy for the treatment cancers, such leukaemias. The therapeutic response to small molecule inhibitors Bromodomain-Containing Proteins (BRD), BRD2 and BRD4, P300/cAMP-response element binding protein (CBP) Cyclin Dependent Kinases (CDKs), is generally attributed selective disruption oncogenic gene expression driven by enhancers, super-enhancers (SEs) lineage-specific factors (TFs), including
Abstract Activating FMS-like tyrosine kinase 3 ( FLT3 ) mutations occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The limited clinical efficacy inhibitor monotherapy has highlighted the need for alternative therapeutic targets treatments FLT3-mutant AML. Using human murine models MLL-rearranged AML harbouring internal tandem duplication (FLT3-ITD) primary patient samples, we have demonstrated that FLT3-ITD promotes serine uptake...
Abstract Cyclin-dependent kinase 9 (Cdk9) is a serine/threonine that regulates elongation of transcription through phosphorylation RNA polymerase II at serine 2 (pSer2-RNAPII). Transient inhibition Cdk9 results in modulation genes with short-lived transcripts and labile proteins, thereby representing potential therapeutic opportunity tumors dependent upon oncogenes fitting these criteria. Mcl1, an anti-apoptotic protein has been linked to increased survival chemotherapy resistance various...
<p>Supplementary Table S1</p>
<p>Supplementary Figures 1-12</p>
<p>Supplementary Figures 1-12</p>
<p>Supplementary Table S1</p>