A5029863354- Acute Myeloid Leukemia Research
- Endoplasmic Reticulum Stress and Disease
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Chronic Lymphocytic Leukemia Research
- Retinoids in leukemia and cellular processes
- Acute Lymphoblastic Leukemia research
- Histone Deacetylase Inhibitors Research
- Chronic Myeloid Leukemia Treatments
- Cellular transport and secretion
- NF-κB Signaling Pathways
- Cancer-related Molecular Pathways
- Multiple Myeloma Research and Treatments
- Renal and related cancers
- Epigenetics and DNA Methylation
- Immune Cell Function and Interaction
- Cell death mechanisms and regulation
- CRISPR and Genetic Engineering
- Genetics and Neurodevelopmental Disorders
- Hematopoietic Stem Cell Transplantation
- Erythrocyte Function and Pathophysiology
- Phagocytosis and Immune Regulation
- Immune Response and Inflammation
- RNA Interference and Gene Delivery
- CAR-T cell therapy research
University of Glasgow
2015-2024
Blood Cancer UK
2013-2024
University of Nebraska at Omaha
2023
Science Oxford
2023
University College Cork
2000-2012
Cancer Research Institute
2006-2010
University of Pennsylvania
2003-2010
UPMC Hillman Cancer Center
2006-2007
Sidney Kimmel Cancer Center
2003-2006
Abramson Cancer Center
2006
Genetic inactivation of Notch signaling in CD4−CD8− double-negative (DN) thymocytes was previously shown to impair T cell receptor (TCR) gene rearrangement and cause a partial block CD4+CD8+ double-positive (DP) thymocyte development mice. In contrast, vitro cultures suggested that absolutely required for the generation DP independent pre-TCR expression activity. To resolve respective role pre-TCR, we inhibited Notch-mediated transcriptional activation vivo with green fluorescent...
Menin is the product of tumor suppressor gene Men1 that mutated in inherited syndrome multiple endocrine neoplasia type 1 (MEN1). has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltransferases including mixed lineage leukemia proteins regulate homeobox ( Hox ) expression vitro . Using conditional knockout mice, we have investigated requirement for menin hematopoiesis and myeloid transformation. excision causes reduction Hoxa9 expression, colony formation...
Trib1, Trib2, and Trib3 are mammalian homologs of Tribbles, an evolutionarily conserved Drosophila protein family that mediates degradation. Tribbles proteins function as adapters to recruit E3 ubiquitin ligases enhance ubiquitylation the target promote its Increased Trib1 Trib2 mRNA expression occurs in human myeloid leukemia induces acute mice, whereas has not been associated with leukemia. Given high degree structural conservation among members, we directly compared 3 hematopoietic cells...
Abstract Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53 , encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate p53, and BET (BETi), targeting BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i BETi towards cell...
Covalent EGFR family inhibitors bind to and induce the degradation of pseudokinase TRIB2 kill cancer cells.
Therapeutic approaches which aim to target Acute Myeloid Leukaemia through enhancement of patients' immune responses have demonstrated limited efficacy date, despite encouraging preclinical data. Examination AML patients treated with azacitidine (AZA) and vorinostat (VOR) in a Phase II trial, an increase the expression Cancer-Testis Antigens (MAGE, RAGE, LAGE, SSX2 TRAG3) on blasts that these can be recognised by circulating antigen-specific T cells. Although cells potential activated...
Abstract Acute myeloid leukaemia (AML) affects children and adults of all ages. AML remains one the major causes death in with cancer for relapse is most common cause death. Here, by modelling vivo we demonstrate that discriminated age cell origin. Young cells give rise to myeloid, lymphoid or mixed phenotype acute leukaemia, whereas adult exclusively AML, a shorter latency. Unlike adult, young do not remodel bone marrow stroma. Transcriptional analysis distinguishes upregulation immune...
The transcription factor NF-ĸB is a master regulator of the innate immune response and plays central role in inflammatory diseases by mediating expression pro-inflammatory cytokines. Ubiquitination-triggered proteasomal degradation DNA-bound strongly limits its target genes. Conversely, USP7 (deubiquitinase ubiquitin-specific peptidase 7) opposes activities E3 ligases, stabilizes NF-ĸB, thereby promotes NF-ĸB-mediated transcription. Using gene synthetic peptide arrays on membrane support...
Abstract Acute myeloid leukemia (AML) is a blood cancer of the lineage. Its prognosis remains poor, highlighting need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias linked to loss healthy hematopoietic stem progenitor cells (HSPCs). The mechanisms behind HSPC decline are complex still poorly understood. Here, intravital microscopy (IVM) well-established experimental model allows direct observation interactions between malignant in bone marrow...
Summary TRIB 2 is a potent oncogene, elevated in subset of human acute myeloid leukaemias ( AML ) with mixed myeloid/lymphoid phenotype and NOTCH 1 mutations. Although rare , activating mutations occur 50% all T cell lymphoblastic ‐ ALL ). target gene that functions the degradation key proteins modulation MAPK signalling pathways, implicated haematopoietic survival proliferation. This study showed expression level highest lymphoid compartment normal cells, specifically cells. Analysis across...
TRIB2, a serine/threonine pseudokinase identified as an oncogene, is expressed at high levels in the T-cell compartment of hematopoiesis. The proliferation developing thymocytes tightly controlled to prevent leukemic transformation T cells. Here we examine Trib2 loss murine hematopoiesis under steady state and proliferative stress conditions, including genotoxic oncogenic stress. (-/-) show increased proliferation, mice have significantly higher thymic cellularity state. During...