A5072637924- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Acute Myeloid Leukemia Research
- Immune cells in cancer
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer-related Molecular Pathways
- Cytokine Signaling Pathways and Interactions
- Hematopoietic Stem Cell Transplantation
- Eosinophilic Disorders and Syndromes
- Acute Lymphoblastic Leukemia research
- RNA Interference and Gene Delivery
- Phagocytosis and Immune Regulation
- 3D Printing in Biomedical Research
- Immunodeficiency and Autoimmune Disorders
- Immune Cell Function and Interaction
- Lymphoma Diagnosis and Treatment
- Nuclear Receptors and Signaling
- Protein Degradation and Inhibitors
- Immune Response and Inflammation
- Galectins and Cancer Biology
- Single-cell and spatial transcriptomics
- Kruppel-like factors research
- Protein Tyrosine Phosphatases
- Pluripotent Stem Cells Research
- Cellular Mechanics and Interactions
University of Glasgow
2016-2025
Blood Cancer UK
2013-2024
Gartnavel General Hospital
2013-2024
Royal Alexandra Hospital
2013
Université Paris Cité
2013
Centre National de la Recherche Scientifique
2013
ManRos Therapeutics (France)
2013
University of Ulster
2008
University of Bath
2001-2004
University College London
1993-1999
The maintenance of murine embryonic stem (ES) cell self-renewal is regulated by leukemia inhibitory factor (LIF)-dependent activation signal transducer and activator transcription 3 (STAT3) LIF-independent mechanisms including Nanog, BMP2/4, Wnt signaling. Here we demonstrate a previously undescribed role for phosphoinositide 3-kinases (PI3Ks) in regulation ES self-renewal. Treatment with the reversible PI3K inhibitor, LY294002, or more specific inhibition class I(A) via expression dominant...
BackgroundCells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses promote trophic signaling pathways. Paradoxically, because of potential cause death tumor thereby militate against malignant disease progression, both tumor-associated macrophages (TAMs) often associated with poor prognosis in cancer. We hypothesized that, progression disease, constitutive...
Multicellular spheroids are an established system for three-dimensional cell culture. Spheroids typically generated using hanging drop or non-adherent culture; however, emerging technique is to use magnetic levitation. Herein, mesenchymal stem were nanoparticles and subsequently cultured within a type I collagen gel, with view towards developing bone marrow niche environment. Cells loaded nanoparticles, suspended beneath external magnet, inducing self-assembly of multicellular spheroids. in...
Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) myeloid (CML). We set out elucidate role of Hh signaling CP-CML and determine if inhibition signaling, through smoothened (SMO), was an effective strategy target LSC. Assessment gene protein expression demonstrated that is activated CD34(+) stem/progenitor cells. LDE225 (Sonidegib), small molecule,...
The introduction of BCR-ABL tyrosine kinase inhibitors has revolutionized the treatment chronic myeloid leukemia (CML). A major clinical aim remains identification and elimination low-level disease persistence, termed "minimal residual disease". phenomenon persistence suggests that despite targeted therapeutic approaches, BCR-ABL-independent mechanisms exist which sustain survival leukemic stem cells (LSCs). Although other markers a primitive CML LSC population have been identified in...
Summary Clonal analysis using X‐chromosome inactivation patterns of the hypoxanthine phosphoribosyl transferase (HPRT) and phosphoglycerate kinase (PGK) genes has been used in assessment haematological malignancies. In many analyses normal haemopoietic tissue or constitutive DNA from each individual not readily available it assumed that when ratio percentage two alleles remaining after differential methylation enzyme digestion is >3/1 then an oligoclonal/monoclonal population cells...
The bone marrow niche represents a specialized environment that regulates mesenchymal stem cell quiescence and self-renewal, yet fosters migration differentiation upon demand. An in vitro model embodies these features would open up the ability to perform detailed study of behavior. In this paper we present simple marrow-like model, which comprises nanomagnetically levitated cells cultured as multicellular spheroids within type I collagen gel. maintained are nestin positive remain quiescent...
Haematopoiesis occurs in the bone marrow (BM), within a specialised microenvironment referred to as stem cell niche, where haematopoietic cells (HSCs) reside and are regulated for quiescence, self-renewal differentiation through intrinsic extrinsic mechanisms. The BM contains at least two distinctive HSC supportive niches: an endosteal osteoblastic which supports quiescence more vascular/peri-sinusoidal niche that promotes proliferation differentiation. Both associate with supporting...
Novel pharmacological strategies capable of inhibiting pro-oncogenic MDM2 beyond its p53-dependent functions represents an increasingly attractive therapeutic strategy to treating solid and haematological cancers that are depdendent upon MDM2/MDMX, regardless TP53 mutational status. Utilising a novel first-in-class cell-penetrating peptide disruptor homo- heterodimerisation (DRx-098D), we demonstrate the anti-proliferative effect blocking dimerisation against panel human cancer cell lines...
Wnt signaling plays several roles in hematopoiesis, promoting hemopoietic stem cell (HSC) self-renewal, providing proliferative signals for immature progenitors and regulating lineage commitment. To ascertain which proteins receptors are important during hematopoietic development, we used two systems; vitro differentiation of embryonic (ES) cells tissues isolated from sites specific hematopoiesis mouse embryogenesis. Initially genes involved were profiled indicate differentiating ES undergo...
Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within microenvironment of lymphoid organs essential limiting CLL progression ultimately developing a cure.We assessed potency cyclin-dependent kinase (CDK) inhibitor CR8, roscovitine analog, to induce apoptosis in primary from distinct prognostic subsets using flow cytometry-based assays....
Cell-cell interactions are vital for numerous biological processes including development, differentiation, and response to inflammation. Currently, most methods studying on scRNA-seq level based curated databases of ligands receptors. While those useful, they limited our current knowledge. Recent advances in single cell protocols have allowed physically interacting cells be captured, as such we the potential study a complemantary way without relying prior We introduce new method Latent...
The generation of hematopoietic stem cells (HSCs) during development is a complex process linked to morphogenic signals. Understanding this important for regenerative medicine applications that require in vitro production HSC. In study we investigated the effects canonical Wnt/β-catenin signaling early embryonic differentiation and specification using an cell system. Our data clearly demonstrates following induction, Wnt induces strong mesodermal program whilst maintaining degree stemness...
A fundamental property of hematopoietic stem cells (HSCs) is the ability to self-renew. This a complex process involving multiple signal transduction cascades which control fine balance between self-renewal and differentiation through transcriptional networks. Key activators/regulators include chemokines, cytokines morphogens are expressed in bone marrow niche, either paracrine or autocrine fashion, modulate cell behaviour. Increasing evidence suggests that downstream signaling pathways...
Cells directly probe and respond to the physicomechanical properties of their extracellular environment, a dynamic process which has been shown play key role in regulating both cellular adhesive processes differential function. Recent studies indicate that stem cells show lineage-specific differentiation when cultured on substrates approximating stiffness profiles specific tissues. Although tissues are associated with range Young's modulus values for bulk rigidity, at subcellular level,...
Abstract Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via cell transplantation. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders clinical utility. Previous developments using stromal feeder layers, defined media cocktails, bioengineering have enabled HSC expansion culture, but mostly short-term HSCs progenitor populations at the expense naive LT-HSCs. Here, we report creation a bioengineered...
Identifying novel players of the pluripotency gene regulatory network centered on Oct4, Sox2, and Nanog as well delineating interactions within complex is key to understanding self-renewal early cell fate commitment embryonic stem cells (ESC). While overexpression transcriptional regulator Cited2 sustains ESC pluripotency, its role in functions remains unclear. Here, we show that important for proliferation, survival, mouse ESC. We position by defining Nanog, Tbx3, Klf4 direct targets. also...
Abstract Background Despite improved patient outcome using tyrosine kinase inhibitors (TKIs), chronic myeloid leukaemia (CML) patients require life-long treatment due to leukaemic stem cell (LSC) persistence. LSCs reside in the bone marrow (BM) niche, which they modify their advantage. The BM provides oncogene-independent signals aid LSC survival and quiescence. bone-morphogenetic pathway (BMP) is one identified be highly deregulated CML, with high levels of BMP ligands detected BM,...