Andrea PepperBrighton and Sussex Medical School | BSMS
Andrea Pepper
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Publications (112)
Genetic heterogeneity and co-occurring driver mutations impact clinical outcomes in blood cancers, but predicting the emergent effect of co-occurring mutations that impact multiple complex and interacting signalling networks is challenging. Here, we used mathematical models to predict the impact of co-occurring mutations on cellular signalling and...
Scoring systems designed to improve the accuracy of prognostication in chronic lymphocytic leukemia (CLL) usually rely on discretized/dichotomic values of the clinical and biological variables. Here we analyzed the immunophenotypic and (immuno)genetic profiles of 2,243 CLL patients with Rai stage 0-I-II, by applying unsupervised machine learning me...
Genetic heterogeneity and co-occurring driver mutations contribute to poor clinical outcomes in cancer. However, the impact of multiple mutations on complex signalling networks is not easily predicted. We found that, by placing mutations into their cellular context, multi-scale agent- based mathematical models could predict how genetic events combi...
In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphom...
Introduction
Improving treatments for Diffuse Large B-Cell Lymphoma (DLBCL) is challenged by the vast heterogeneity of the disease. Nuclear factor-κB (NF-κB) is frequently aberrantly activated in DLBCL. Transcriptionally active NF-κB is a dimer containing either RelA, RelB or cRel, but the variability in the composition of NF-κB between and within...
Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia in the western world. Despite the positive clinical effects of new targeted therapies, CLL still remains an incurable and refractory disease and resistance to treatments are commonly encountered. The Nuclear Factor-Kappa B (NF-kB) transcription factor has been implicated in t...
In healthy cells, pro- and anti-apoptotic BCL2 family and BH3-only proteins are expressed in a delicate equilibrium. In contrast, this homeostasis is frequently perturbed in cancer cells due to the overexpression of anti-apoptotic BCL2 family proteins. Variability in the expression and sequestration of these proteins in Diffuse Large B cell Lymphom...
Pathogenesis in chronic lymphocytic leukemia (CLL) is strongly linked to the potential for leukemic cells to migrate to and proliferate within lymph-nodes. Previous in vivo studies suggest that all leukemic cells participate in cycles of migration and proliferation. In vitro studies, however, have shown heterogeneous migration patterns.
To investig...
The retention and re-migration of Chronic Lymphocytic Leukemia cells into cytoprotective and proliferative lymphoid niches is thought to contribute to the development of resistance, leading to subsequent disease relapse. The aim of this study was to elucidate the molecular processes that govern CLL cell migration to elicit a more complete inhibitio...
In this study, we evaluated an NF-κB inducing kinase (NIK) inhibitor, CW15337, in primary chronic lymphocytic leukemia (CLL) cells, CLL and multiple myeloma (MM) cell lines and normal B- and T-lymphocytes. Basal NF-κB subunit activity was characterized using an enzyme linked immunosorbent assay (ELISA), and the effects of NIK inhibition were then a...
CLL remains incurable despite BCR-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate, which is activated by unmethylated CpG-DNA. Here, we show that plasma from CLL patients contains significantly m...
Background - Although there has been a revolution in the treatment of chronic lymphocytic leukemia (CLL), the challenge remains to identify the right drugs for the right patients. It is widely accepted that CIT, including the 'gold standard' fludarabine, cyclophosphamide and rituximab (FCR), is contraindicated for patients with TP53 disruption and,...
Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are incurable hematological malignancies that are pathologically linked with aberrant NF-κB activation. In this study, we identified a group of novel C8-linked benzofused Pyrrolo[2,1-c][1,4]benzodiazepines (PBD) monomeric hybrids capable of sequence-selective inhibition of NF-κB with low...
Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build‐up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion...
Purpose of review:
Acute myeloid leukaemia (AML) is a heterogeneous malignancy for which treatment options remain suboptimal. It is clear that a greater understanding of the biology of the AML niche will enable new therapeutic strategies to be developed in order to improve treatment outcomes for patients.
Recent findings:
Recent evidence has hig...
Despite the success of autologous anti-CD19 CAR T cell therapy in B-Acute lymphoblastic leukaemia (B-ALL) and Diffuse Large B Cell Lymphoma (DLBCL), treatment failures occur. One contributing factor may be the intrinsic T cell fitness of the CAR T cell product that is influenced by the underlying malignancy and prior treatments. With the advent of...
CD4+ T-follicular helper cells are essential for the survival, proliferation, and differentiation of germinal center B-cells and have been implicated in the pathogenesis of follicular lymphoma. To further define the role of these cells in follicular lymphoma, we used multiparameter confocal microscopy to compare the architecture of normal and neopl...
Background
Follicular lymphoma (FL) is a germinal centre (GC) B‐cell neoplasm that is dependent on interactions with its non‐malignant tumour microenvironment (TME). Follicular helper T‐cells (Tfh) play a pivotal role in supporting healthy GC B‐cell development, proliferation, and maturation. In FL, Tfh are present in similar proportions to reactiv...
Acute Myeloid Leukaemia(AML) is an aggressive blood cancer affecting both children and adults. It is caused by failure in myeloid precursor cell differentiation into functional granulocytes resulting in accumulation of immature/ineffective leukaemic cells in the bone marrow (BM). Normal haemopoiesis fails and patients suffer infections, bleeding an...
Acetylsalicylic acid, or aspirin, is one of the most common non-steroidal anti-inflammatory drugs, which has been shown to have anti-cancer effects. However, high doses are needed making it unsuitable as an oncology agent. We have previously reported increased potency in a series of hydroxybenzoate zinc (HBZn) aspirin analogues. Here we show that 3...
Patient derived anti-CD19 chimeric antigen receptor-T (CAR-T) cells are a powerful tool in achieving a complete remission in a range of B-cell malignancies, most notably B-acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, there are limitations, including inability to manufacture CAR-T cells from the patient’s...
Key Points
Basal intracellular Ca2+ levels and migration increase with higher CD38 expression in CLL cells. Rap1 and the Rap1 guanine-nucleotide exchange factor RasGRP2 are required for CLL migration and regulated by CD38 levels.
B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand-receptor complexes. In the present study we inv...
Ligation of the B-cell receptor (BCR) results in activation of intracellular signaling as well as internalization and processing of ligand/receptor complexes. BCR responsiveness has been shown to vary markedly between patients with chronic lymphocytic leukaemia (CLL) and is linked to prognosis. Despite the central importance of BCR signaling in CLL...
Key Points
LN-derived CLL cells have increased capacity for T-cell activation and superior immune synapse formation compared with those from PB. Enhanced CLL cell immunologic function is also linked to PB circulating cells with the propensity to migrate.
It is now generally believed that proliferation of the neoplastic clone in chronic lymphocytic leukemia (CLL) takes place in lymphoid tissues where interactions involving the B-cell receptor (BCR) and other microenvironmental elements take place. Previous studies using in-vivo labelling with deuterated water have shown that recently proliferated em...
Hydroxybenzoate (HB) compounds have shown their significance in inducing apoptosis in primary chronic lymphocytic leukemia (CLL) and cancer cell lines, including HT-1080. The current study focuses on assessing the effects of 2-, 3- and 4-hydroxybenzoate calcium (HBCa) compounds on MCF-10A, MDA-MB231 and MCF-7 epithelial breast cell lines. The HBCa-...
The tumor microenvironment plays a central role in the pathogenesis of follicular lymphoma (FL) and has been shown to influence prognosis. The biological basis for this and the contribution of individual cell types however, remain unclear. In this study we compared the cellular content and structure of neoplastic follicles in FL with their normal c...
Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Key Points
We have developed a novel in vitro system to model how shear force and transient interaction with endothelial cells alter chronic lymphocytic leukemia cell phenotype and behavior. We have used our model to investigate chronic lymphocytic leukemia cell migration and have determined the critical role for integrin α4β1 in this process.
It is now widely accepted that in chronic lymphocytic leukaemia (CLL), proliferation of the malignant B cell clone takes place in pseudofollicles positioned within lymphoid tissue. This complex environment is believed to provide CLL cells with signals necessary for survival and expansion. In recent years the role for T cells in these processes has...
It has recently become clear that B cell receptor (BCR) activation plays an important role in the pathogenesis of chronic lymphocytic leukaemia (CLL); a fact that is underlined by the marked efficacy of drugs that inhibit components of this pathway. Although the underlying mechanisms remain unclear, CLL BCRs have been shown to recognize a variety o...
It is now well established that CLL is a highly proliferative disease with replication restricted to lymphoid tissue microenvironments. There is good evidence that interactions involving activated CD4+ T cells influence proliferation of the neoplastic B-cell clone. In this study we investigated the paradox that, whilst chronically activated T cells...
There is growing evidence that lymphocyte trafficking contributes to the clinical course of chronic lymphocytic leukemia (CLL). However, no in vitro models exist to quantify migration from the peripheral vasculature or establish the key molecular events that drive this process. We have therefore established and characterized a novel dynamic in vitr...
Interactions in the tumour microenvironment can promote chronic lymphocytic leukaemia (CLL) cell survival, proliferation and drug resistance. A detailed comparison of three co-culture systems designed to mimic the CLL lymph node and vascular microenvironments were performed; two were mouse fibroblast cell lines transfected with human CD40LG or CD31...
Non-steroidal anti-inflammatory drugs have been shown to induce apoptosis in primary B-cell chronic lymphocytic leukaemia (CLL) cells, but the molecular mechanisms that underpin this observation have not been fully elucidated. Here, we have analysed the effect two novel aspirin analogues, 2-hydroxy benzoate zinc (2HBZ) and 4-hydroxy benzoate zinc (...
Progressive chronic lymphocytic leukaemia is characterized by the accumulation of neoplastic B-cells in the tissues and correlates with the expression of prognostic biomarkers, such as CD38, CD49d and matrix metalloproteinase-9 (MMP9), which are involved in migration and tissue invasion. In this study we investigated the physical relationship betwe...
915
In this study we put forward a novel approach to investigate the T cell compartment of chronic lymphocytic leukaemia (CLL). The role of T cells in the pathobiology of CLL has become the subject of much research due to compelling evidence that CLL is derived from antigen experienced B cells that are subject to ongoing activation. The malignant p...
The world of chronic lymphocytic leukemia (CLL) research is awash with prognostic markers. However, very few of the current group play a clearly defined role in the pathology of this disease and even fewer represent a tractable therapeutic target. One such marker that fulfils both of these criteria is the integrin CD49d. This molecule been implicat...
Chronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis in vitro, suggesting that the in vivo microenvironment provides crucial antiapoptotic signals. Overexpression of the antiapoptotic proteins Bcl-2 and Mcl-1 is a hallmark of CLL, and their expression is further enhanced in the lymphoid tissues. However, the high levels of Mcl-1 found...
Bcl-2 family proteins have long been implicated in the pathology of chronic lymphocytic leukaemia (CLL). Indeed, a number of these proteins have been shown to have prognostic importance in this disease. The precise ways in which these proteins impact upon CLL and the ways in which they are regulated remain incompletely resolved. However, significan...
2334
Poster Board II-311
The outcome for patients with Chronic Lymphocytic Leukemia (CLL) is highly variable and correlates with clinical parameters such as disease stage, as well as various biological markers that reflect the genomic, phenotypic and functional properties of the tumor and its microenvironment. CD38, Cd49d and ZAP-70 are three such...
2362
Poster Board II-339
There is growing evidence that interactions in the tumour microenvironment promote the survival, proliferation and drug resistance of primary chronic lymphocytic leukaemia (CLL) cells. Furthermore, progressive CLL is frequently associated with lymphadenopathy, pointing to a crucial role for signals emanating from the tissue...
Chronic lymphocytic leukemia (CLL) is a highly variable disorder whose outcome can be predicted by a number of clinical and biological markers. The level of expression of CD38 by peripheral blood leukemic cells is one such prognostic biomarker however despite widespread use in clinical practice, its role in the pathogenesis of CLL remains unclear a...
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with a highly variable outcome. The prognosis of patients with CLL may be predicted using a number of biomarkers, including the level of CD38 expression at the leukemic cell surface. This study investigates the hypothesis that CD38 expression by CLL cells reflects interactions with...
Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Langerhans cells (LCs) are antigen presenting cells found in the epidermis. They are thought to originate from bone marrow precursors although studies in mice suggest they have the ability to self renew in situ. Murine models have also shown that recipient LCs are required for the development of acute graft versus host disease (GVHD) following allo...
High levels of CD38 expression in B-cell chronic lymphocytic leukaemia (B-CLL) confer a poor prognosis. Although its role in B-CLL is unknown, signalling through CD38 has been implicated in cell survival, trafficking and proliferation. Since proliferation in B-CLL is thought to take place within both bone marrow (BM) and secondary lymphoid tissue,...
Immune dysfunction is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) which occurs through loss of normal cell function as the malignant clone expands, as a result of therapy or because of immunoregulatory properties of the tumor itself. It has previously been shown that B-CLL cells are poor stimulators of the allogeneic mixed lymphocyte...
We showed previously that tumor-derived supernatant (TSN) from acute myeloid leukemia (AML) myeloblasts inhibits peripheral blood T cell activation and proliferation, rendering the T cells functionally incompetent. We show here that the AML TSN also significantly delays apoptosis of both resting and stimulated T cells, as judged by reduction in ann...
Interactions between CD40L (CD154) and its receptor CD40, are of central importance in T-cell mediated B-cell activation, proliferation and isotype switching and the regulation of antigen presentation by dendritic cells. Peripheral blood T lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) have an acquired defect of activati...
Primary hematopoietic cells are relatively refractory to DNA transfection methodologies. This is particularly so when they are quiescent or terminally differentiated and no longer able to divide. However, whole proteins can be introduced into such cells by protein transduction. We have modified the protein transduction domain (PTD) from the HIV-TAT...