ORCID Profile
0000-0003-1198-6373
Current Organisations
Edith Cowan University
,
University of Western Australia
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Publisher: Elsevier BV
Date: 02-2012
Publisher: Informa UK Limited
Date: 08-2009
DOI: 10.1128/MCB.00090-09
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.CCELL.2020.05.014
Abstract: Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2021
DOI: 10.1038/S41467-021-22101-7
Abstract: Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene lified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC -dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC -overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC lification.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
DOI: 10.1038/S41375-018-0354-Z
Abstract: Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem rogenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2018
Publisher: Elsevier BV
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 07-10-2022
DOI: 10.1038/S41389-022-00435-1
Abstract: The MYC proto-oncogene ( MYC ) is one of the most frequently overexpressed genes in breast cancer that drives cancer stem cell-like traits, resulting in aggressive disease progression and poor prognosis. In this study, we identified zinc finger transcription factor 148 ( ZNF148 , also called Zfp148 and ZBP-89) as a direct target of MYC. ZNF148 suppressed cell proliferation and migration and was transcriptionally repressed by MYC in breast cancer. Depletion of ZNF148 by short hairpin RNA (shRNA) and CRISPR/Cas9 increased triple-negative breast cancer (TNBC) cell proliferation and migration. Global transcriptome and chromatin occupancy analyses of ZNF148 revealed a central role in inhibiting cancer cell de-differentiation and migration. Mechanistically, we identified the Inhibitor of DNA binding 1 and 3 ( ID1, ID3 ), drivers of cancer stemness and plasticity, as previously uncharacterized targets of transcriptional repression by ZNF148. Silencing of ZNF148 increased the stemness and tumorigenicity in TNBC cells. These findings uncover a previously unknown tumor suppressor role for ZNF148, and a transcriptional regulatory circuitry encompassing MYC, ZNF148, and ID1/3 in driving cancer stem cell traits in aggressive breast cancer.
Publisher: Wiley
Date: 16-07-2021
DOI: 10.1111/CEA.13982
Abstract: Anaphylaxis is a severe, potentially life‐threatening allergic reaction driven primarily by the activation of mast cells. We still fail to understand factors underlying reaction severity. Furthermore, there is currently no reliable diagnostic test to confirm anaphylaxis in the emergency department (ED). This study sought to explore gene expression changes associated with anaphylaxis severity in peripheral blood leucocytes and evaluate biomarker potential. Microarray analysis (total RNA) was performed using peripheral blood s les from ED patients with moderate ( n = 6) or severe ( n = 12) anaphylaxis and sepsis ( n = 20) at presentation (T0) and one hour later (T1). Results were compared between groups and healthy controls ( n = 10 and n = 11 matched to anaphylaxis and sepsis patients, respectively). Changes in gene expression were determined using R programming language, and pathway analysis applied to explore biological processes and pathways associated with genes. Differentially expressed genes were validated in an independent cohort of anaphylaxis ( n = 30) and sepsis ( n = 20) patients, and healthy controls ( n = 10), using quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR). Significant up‐regulation of small nucleolar RNAs (snoRNAs) was demonstrated in anaphylaxis compared to sepsis patients in the microarray cohort, at T0 and T1. qRT‐PCR analysis of the validation cohort showed five genes: SNORD61 , SNORD8 , SNORD69 , SNORD119 and HIST1H1D to be significantly up‐regulated (adjusted p 0.05) in severe anaphylaxis compared to sepsis. Seven genes ( SNORD61 , SNORD8 , SCARNA21 , SNORD69 , SNORD110 , SNORD119 and SNORD59A ) were significantly up‐regulated (adjusted p 0.05) in severe anaphylaxis compared to healthy controls. This study demonstrates for the first time the unique involvement of snoRNAs in the pathogenesis of anaphylaxis and suggests they are not a general feature of systemic inflammation. Further investigation of snoRNA expression in anaphylaxis could provide insights into disease pathogenesis. SnoRNAs are up‐regulated during acute anaphylaxis in humans and could potentially be used as biomarkers of severe anaphylaxis.
Publisher: Springer Science and Business Media LLC
Date: 09-09-2021
DOI: 10.1038/S41598-021-97190-X
Abstract: RNA-based therapeutics are emerging as innovative options for cancer treatment, with microRNAs being attractive targets for therapy development. We previously implicated microRNA-642a-5p (miR-642a-5p) as a tumor suppressor in prostate cancer (PCa), and here we characterize its mode of action, using 22Rv1 PCa cells. In an in vivo xenograft tumor model, miR-642a-5p induced a significant decrease in tumor growth, compared to negative control. Using RNA-Sequencing, we identified gene targets of miR-642a-5p which were enriched for gene sets controlling cell cycle downregulated genes included Wilms Tumor 1 gene (WT1), NUAK1, RASSF3 and SKP2 and upregulated genes included IGFBP3 and GPS2. Analysis of PCa patient datasets showed a higher expression of WT1, NUAK1, RASSF3 and SKP2 and a lower expression of GPS2 and IGFBP3 in PCa tissue compared to non-malignant prostate tissue. We confirmed the prostatic oncogene WT1, as a direct target of miR-642a-5p, and treatment of 22Rv1 and LNCaP PCa cells with WT1 siRNA or a small molecule inhibitor of WT1 reduced cell proliferation. Taken together, these data provide insight into the molecular mechanisms by which miR-642a-5p acts as a tumor suppressor in PCa, an effect partially mediated by regulating genes involved in cell cycle control and restoration of miR-642-5p in PCa could represent a novel therapeutic approach.
Publisher: Elsevier BV
Date: 10-2010
Publisher: Springer Science and Business Media LLC
Date: 18-11-2014
DOI: 10.1038/NCOMMS6490
Abstract: Both transcriptional and epigenetic regulations are fundamental for the control of eukaryotic gene expression. Here we perform a compendium analysis of large sequencing data sets to elucidate the regulatory logic of global gene expression programs in mouse embryonic stem (ES) cells. We define four major classes of DNA-binding proteins (Core, PRC, MYC and CTCF) based on their target co-occupancy, and discover reciprocal regulation between the MYC and PRC classes for the activity of nearly all genes under the control of the CpG island (CGI)-containing promoters. This CGI-dependent regulatory mode explains the functional segregation between CGI-containing and CGI-less genes during early development. By defining active enhancers based on the co-occupancy of the Core class, we further demonstrate their additive roles in CGI-containing gene expression and cell type-specific roles in CGI-less gene expression. Altogether, our analyses provide novel insights into previously unknown CGI-dependent global gene regulatory modes.
Publisher: Informa UK Limited
Date: 04-2008
DOI: 10.1128/MCB.01945-07
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2016
DOI: 10.1158/1538-7445.SABCS15-P2-06-01
Abstract: The recent integration of both genomic and transcriptomic datasets have added a further dimension to the landscape of breast cancer (BrCa) subtyping, defining novel functional subgroups with distinctive oncogenic drivers that carry important implications for therapy. This integrative clustering has unveiled a novel subtype of hormone receptor positive (HR+) BrCa associated with high proliferation and very poor survival characterised by copy number lification and overexpression of a cluster of candidate oncogenic drivers at the 11q13.5-14 locus (1). At the heart of this licon we have demonstrated the selective overexpression of C11orf67/AAMDC (Adipogenesis associated Mth938 domain containing) which encodes a hypothetical protein of 122 aa with unknown function. In a pilot tissue microarray of 75 BrCa cases C11orf67 lification and expression were significantly correlated with hormone receptor positivity. These positive cases also demonstrated high risk features with 75% demonstrating lymph node involvement. In functional elucidation studies knockdown of C11orf67 in the highly expressing T47D cell line lead to decreased cell proliferation, cell migration, anchorage independent cell growth and induction of senescence. T47D xenografts with stable shRNA-induced C11orf67 knockdowns introduced into BALB/c mice showed significantly lower tumour volumes relative to T47D with empty vector. A genome wide analysis of these T47D-C11orf67 shRNA cells compared to T47D-empty vector cells using the Illumina HumanHT-12 platform demonstrated 40 differentially expressed genes. Network analysis revealed a proliferation node, enriched in cell cycle proteins, and a metabolic node comprising several biosynthetic enzymes such as MTHFD1L involved in one-carbon folate metabolism. Supporting this link and pointing to potential utility in chemotherapy selection, induction of ectopic C11orf67 expression in MCF7 cells increased sensitivity to fluorouracil and methotrexate but not to paclitaxel. Investigating potential novel binding partners and effectors, in yeast two hybrid screening C11orf67 was a found to associate strongly with RABGAP1L, a protein involved in controlling GTPase signalling, protein trafficking, and autophagy. Exploring the molecular cues that control C11orf67 expression, our data suggest the locus is regulated by transcription factors associated with high proliferation and metabolic control, notably Myc and NFkB, as well as HRs. E2 lead to a significant down-regulation of C11orf67 in T47D cells, which was reversed by the antiestrogen drug tamoxifen, whereas PG significantly increased C11orf67 levels. In keeping with this MCF7 cells ectopically expressing C11orf67 were resistant to the anti-proliferative effects of tamoxifen compared to the parent cell line. These observations endorse C11orf67 as a novel oncogenic driver with exciting therapeutic potential, which could serve to distinguish the HR+ tumours at high risk of relapse and guide both the selection of current chemotherapeutical and endocrine treatments as well as the design of future precision therapeutics, notably anti-folate/one carbon drugs and novel endocrine agents. References 1. Curtis et al. Nature. 2012 Jun 21 (7403):346-52. Citation Format: Redfern A, Rashwan R, Sorolla A, Ratajska M, Kardas I, Kuzniacka A, Parry J, Curtis C, Woo A, Sgro A, Biernat W. Characterisation of C11orf67, an oncogenic driver in a new subtype of aggressive endocrine receptor positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2016 (4 Suppl):Abstract nr P2-06-01.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 21-02-2019
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1435
Abstract: Mechanisms underlying the anaphylactic reaction in humans are not fully understood. Here, we aimed at improving our understanding of anaphylaxis by investigating gene expression changes. Microarray data set GSE69063 was analysed, describing emergency department (ED) patients with severe anaphylaxis ( n = 12), moderate anaphylaxis ( n = 6), sepsis ( n = 20) and trauma ( n = 11). S les were taken at ED presentation (T0) and 1 h later (T1). Healthy controls were age and sex matched to ED patient groups. Gene expression changes were determined using limma , and pathway analysis applied. Differentially expressed genes were validated in an independent cohort of anaphylaxis patients ( n = 31) and matched healthy controls ( n = 10), using quantitative reverse transcription‐polymerase chain reaction. Platelet aggregation was dysregulated in severe anaphylaxis at T0, but not in moderate anaphylaxis, sepsis or trauma. Dysregulation was not observed in patients who received adrenaline before T0. Seven genes ( GATA1 (adjusted P‐ value = 5.57 × 10 −4 ), TLN1 (adjusted P‐ value = 9.40 × 10 −4 ), GP1BA (adjusted P ‐value = 2.15 × 10 −2 ), SELP (adjusted P ‐value = 2.29 × 10 −2 ), MPL (adjusted P ‐value = 1.20 × 10 −2 ), F13A1 (adjusted P ‐value = 1.39 × 10 −2 ) and SPARC (adjusted P ‐value = 4.06 × 10 −2 )) were significantly downregulated in severe anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. One gene ( TLN1 (adjusted P ‐value = 1.29 × 10 −2 )) was significantly downregulated in moderate anaphylaxis patients who did not receive adrenaline before ED arrival, compared with healthy controls. Downregulation of genes involved in platelet aggregation and activation is a unique feature of the early anaphylactic reaction not previously reported and may be associated with reaction severity.
Publisher: Wiley
Date: 2007
DOI: 10.1002/PATH.2258
Abstract: CD30 is a member of the TNF receptor family. Our interest lies in understanding the control of CD30 expression, particularly as its over-expression provides a diagnostic marker for a subset of non-Hodgkin's lymphomas, particularly anaplastic large cell lymphoma (ALCL), and because anti-CD30 treatment has been shown to be efficacious. We have identified a number of regulatory regions, including an Sp1 element in the minimal promoter, and a downstream promoter element that is required for start site selection. The discovery of both an activating AP1 site and an upstream microsatellite that represses transcriptional activity of CD30 suggests that this region is involved in dysregulation of CD30 expression. We have now identified the major microsatellite binding activity as transcription factor Yin Yang 1 by both one-hybrid cDNA library screening and peptide mass fingerprinting. Due to the strong repressive effect of the microsatellite, we also investigated whether microsatellite instability may induce changes in CD30 expression and hence explain the over-expression of CD30 in ALCL. Laser capture microdissection of ALCL biopsies and CD30 microsatellite typing indicated that the neoplastic cells show a high degree of variation, but this does not correlate with high CD30 expression seen in ALCL.
Publisher: Cold Spring Harbor Laboratory
Date: 03-07-2012
Abstract: Hematopoietic development occurs in complex microenvironments and is influenced by key signaling events. Yet how these pathways communicate with master hematopoietic transcription factors to coordinate differentiation remains incompletely understood. The transcription factor RUNX1 plays essential roles in definitive hematopoietic stem cell (HSC) ontogeny, HSC maintenance, megakaryocyte (Mk) maturation, and lymphocyte differentiation. It is also the most frequent target of genetic alterations in human leukemia. Here, we report that RUNX1 is phosphorylated by Src family kinases (SFKs) and that this occurs on multiple tyrosine residues located within its negative regulatory DNA-binding and autoinhibitory domains. Retroviral transduction, chemical inhibitor, and genetic studies demonstrate a negative regulatory role of tyrosine phosphorylation on RUNX1 activity in Mk and CD8 T-cell differentiation. We also demonstrate that the nonreceptor tyrosine phosphatase Shp2 binds directly to RUNX1 and contributes to its dephosphorylation. Last, we show that RUNX1 tyrosine phosphorylation correlates with reduced GATA1 and enhanced SWI/SNF interactions. These findings link SFK and Shp2 signaling pathways to the regulation of RUNX1 activity in hematopoiesis via control of RUNX1 multiprotein complex assembly.
Publisher: American Society of Hematology
Date: 29-09-2011
DOI: 10.1182/BLOOD-2011-03-341446
Abstract: The molecular mechanisms underlying erythroid-specific gene regulation remain incompletely understood. Closely spaced binding sites for GATA, NF-E2/maf, and CACCC interacting transcription factors play functionally important roles in globin and other erythroid-specific gene expression. We and others recently identified the CACCC-binding transcription factor ZBP-89 as a novel GATA-1 and NF-E2/mafK interacting partner. Here, we examined the role of ZBP-89 in human globin gene regulation and erythroid maturation using a primary CD34+ cell ex vivo differentiation system. We show that ZBP-89 protein levels rise dramatically during human erythroid differentiation and that ZBP-89 occupies key cis-regulatory elements within the globin and other erythroid gene loci. ZBP-89 binding correlates strongly with RNA Pol II occupancy, active histone marks, and high-level gene expression. ZBP-89 physically associates with the histone acetyltransferases p300 and Gcn5/Trrap, and occupies common sites with Gcn5 within the human globin loci. Lentiviral short hairpin RNAs knockdown of ZBP-89 results in reduced Gcn5 occupancy, decreased acetylated histone 3 levels, lower globin and erythroid-specific gene expression, and impaired erythroid maturation. Addition of the histone deacetylase inhibitor valproic acid partially reverses the reduced globin gene expression. These findings reveal an activating role for ZBP-89 in human globin gene regulation and erythroid differentiation.
Publisher: Elsevier BV
Date: 06-2002
Publisher: American Society for Clinical Investigation
Date: 07-2013
DOI: 10.1172/JCI40609
Publisher: American Thoracic Society
Date: 03-2013
Publisher: American Society of Hematology
Date: 27-08-2019
DOI: 10.1182/BLOODADVANCES.2018030551
Abstract: Erythroid maturation requires the concerted action of a core set of transcription factors. We previously identified the Krüppel-type zinc finger transcription factor Zfp148 (also called ZBP-89) as an interacting partner of the master erythroid transcription factor GATA1. Here we report the conditional knockout of Zfp148 in mice. Global loss of Zfp148 results in perinatal lethality from nonhematologic causes. Selective Zfp148 loss within the hematopoietic system results in a mild microcytic and hypochromic anemia, mildly impaired erythroid maturation, and delayed recovery from phenylhydrazine-induced hemolysis. Based on the mild erythroid phenotype of these mice compared with GATA1-deficient mice, we hypothesized that additional factor(s) may complement Zfp148 function during erythropoiesis. We show that Zfp281 (also called ZBP-99), another member of the Zfp148 transcription factor family, is highly expressed in murine and human erythroid cells. Zfp281 knockdown by itself results in partial erythroid defects. However, combined deficiency of Zfp148 and Zfp281 causes a marked erythroid maturation block. Zfp281 physically associates with GATA1, occupies many common chromatin sites with GATA1 and Zfp148, and regulates a common set of genes required for erythroid cell differentiation. These findings uncover a previously unknown role for Zfp281 in erythroid development and suggest that it functionally overlaps with that of Zfp148 during erythropoiesis.
No related grants have been discovered for Andrew Woo.