A5029749141- Acute Myeloid Leukemia Research
- Protein Degradation and Inhibitors
- Mast cells and histamine
- Click Chemistry and Applications
- Epigenetics and DNA Methylation
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Cell death mechanisms and regulation
- Genomics and Rare Diseases
- PI3K/AKT/mTOR signaling in cancer
- CAR-T cell therapy research
- Acute Lymphoblastic Leukemia research
- Sarcoma Diagnosis and Treatment
- Ubiquitin and proteasome pathways
- Cardiac tumors and thrombi
- Congenital heart defects research
- Congenital Heart Disease Studies
- Nanoparticles: synthesis and applications
- Connective tissue disorders research
- Nuclear Receptors and Signaling
- Trace Elements in Health
- Cholinesterase and Neurodegenerative Diseases
- Receptor Mechanisms and Signaling
- Sphingolipid Metabolism and Signaling
- Platelet Disorders and Treatments
Washington University in St. Louis
2017-2024
Indiana University School of Medicine
2022-2024
Indiana University – Purdue University Indianapolis
2022-2024
The University of Queensland
2013-2021
Hunter Medical Research Institute
2010-2016
Leukaemia Foundation of Queensland
2016
University of Newcastle Australia
2016
Ottawa Hospital Research Institute
2013
Ottawa Hospital
2004-2013
Children's Medical Research Institute
2013
Abstract Oncogenic mutations of the receptor tyrosine kinase c-KIT play an important role in pathogenesis gastrointestinal stromal tumors, systemic mastocytosis, and some acute myeloid leukemias (AML). Although juxtamembrane commonly detected tumor are sensitive to inhibitors, domain frequently encountered mastocytosis AML confer resistance largely unresponsive targeted inhibition by existing agent imatinib. In this study, we show that cells expressing activated mutants imatinib (V560G) or...
The gene that encodes de novo DNA methyltransferase 3A (DNMT3A) is frequently mutated in acute myeloid leukemia genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% are predicted produce truncated proteins could either activities or function and haploinsufficiency. Here, we demonstrate 3 these mutants truncated, inactive do not dimerize with WT DNMT3A, strongly supporting the haploinsufficiency hypothesis. We...
Abstract Germline pathogenic variants in DNMT3A were recently described patients with overgrowth, obesity, behavioral, and learning difficulties ( D NMT3A O vergrowth S yndrome/DOS). Somatic mutations the gene are also most common cause of clonal hematopoiesis, can initiate acute myeloid leukemia (AML). Using whole genome bisulfite sequencing, we studied DNA methylation peripheral blood cells 11 DOS found a focal, canonical hypomethylation phenotype, which is severe dominant negative R882H...
Exposure to silver is increasing because of nanoparticles in consumer products.Many biological effects entail actions Ag+ (monovalent ions), so we used neuronotypic PC12 cells evaluate the potential for act as a developmental neurotoxicant, using chlorpyrifos (CPF), pesticide known evoke neurotoxicity, positive control comparison.In undifferentiated cells, 1-hr exposure 10 microM inhibited DNA synthesis more potently than did 50 CPF; it also impaired protein but lesser extent its effect on...
Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well β-alanine. Existing reports describe highly variable clinical biochemical phenotype, which can make diagnosis challenge. To date, only three reported cases have been confirmed at the molecular level, through identification homozygous...
// Amanda M. Smith 1, 2, 3, * , Matthew D. Dun Erwin Lee 4 Celeste Harrison 2 Richard Kahl Hayley Flanagan Nikita Panicker Baratali Mashkani 5 Anthony S. Don 6 Jonathan Morris 7 Hamish Toop B. Lock Jason A. Powell 8 Daniel Thomas 8, 9 Mark Guthridge 10 Andrew Moore 11 Leonie K. Ashman Kathryn Skelding Anoop Enjeti 12 Nicole Verrills 1 School of Biomedical Sciences and Pharmacy, University Newcastle, Callaghan, New South Wales, Australia Hunter Medical Research Institute, 3 Current address:...
Mutations in the DNA methyltransferase 3A ( DNMT3A ) gene are most common cause of age-related clonal hematopoiesis (ARCH) older individuals, and among initiating events for acute myeloid leukemia (AML). The frequent mutation AML patients (R882H) encodes a dominant-negative protein that reduces activity by ∼80% cells with heterozygous mutations, causing focal, canonical hypomethylation phenotype; this phenotype is partially recapitulated murine Dnmt3a −/− bone marrow cells. To determine...
Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency
// Amanda M. Smith 1 , 4 * Christine R.C. Zhang Alexandre S. Cristino 6 John P. Grady 5 J. Lynn Fink and Andrew Moore 2 3 The University of Queensland Diamantina Institute, Queensland, Woolloongabba, Australia Oncology Services Group, Children’s Hospital, South Brisbane, Child Health Research Centre, Current address: Washington in Saint Louis, Missouri, United States America Garvan Institute Medical Research, Darlinghurst, Griffith for Drug Discovery, Brisbane Innovation Park, Nathan,...
Significance Keratinocyte carcinomas are the most common malignancies in fair-skinned patients. Increased age and sun exposure important skin cancer risk factors have been associated with a loss of DNA methylation human epidermis. Complete Dnmt3a deficiency mouse creates premalignant state, but mechanisms responsible for this phenomenon not clear. This study demonstrates that murine epidermis causes focal, canonical hypomethylation an increased proportion cells proliferative gene expression...
Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery a rare dominant lethal mutation TPM1, sarcomeric actin-binding protein, eight individuals with large atrial septal defect (ASD) five-generation pedigree. Mice Tpm1 exhibit early embryonic lethality disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show...
CD19-targeted immunotherapies that stimulate a cytotoxic T-cell response have revolutionized the management of B-cell malignancies, specifically relapsed or refractory acute lymphoblastic leukemia (R/ R ALL).Blinatumomab is an anti-CD19 bispecific engager approved for treatment patients with R/R ALL. 1 KTE-X19 autologous chimeric antigen receptor (CAR) therapy under investigation in ZUMA-3 (XXX) phase 1/2 clinical trial (registered at www.clinicaltrials.gov2][3][4][5] Several distinct...
Mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) are most common cause of clonal hematopoiesis and among initiating events acute myeloid leukemia (AML). Studies germline somatic Dnmt3a knockout mice have identified focal, canonical hypomethylation phenotypes hematopoietic cells; however, kinetics methylation loss following acquired DNMT3A inactivation cells is essentially unknown. Therefore, we evaluated a somatic, inducible model loss, show that murine results relatively...
Abstract Malignant cells, including acute myeloid leukaemia (AML), have high protein turnover to support their accelerated cell growth. Aminopeptidases regulate proteolysis, supplying free amino acids for new synthesis. Inhibition of aminopeptidases depletes acids, impairing production, leading impaired growth and proliferation. Hence, aminopeptidase inhibition is particular interest as a therapeutic strategy AML. Tosedostat (CHR-2797) an inhibitor which converted its active metabolite,...
Supplementary Figure 1 from Essential Requirement for PP2A Inhibition by the Oncogenic Receptor c-KIT Suggests Reactivation as a Strategy to Treat c-KIT<sup>+</sup> Cancers