Stem Cell Laboratory
Group Leader: Professor Tariq Enver
Because of their unique biological properties and potential medical importance, stem cells have attracted major scientific, commercial and public interest (Weissman et al, Annu Rev Cell Dev Biol; 17:387-403, 2001). The cell fate options that confront stem cells include self-renewal, differentiation and lineage-specification, programmed cell death and quiescence. Within haematopoiesis, constitutive dysregulation of the balance between these processes is an essential feature of leukaemogenesis. A key challenge is to understand how the different cell fates that confront stem and progenitor cells are selected and co-ordinated; adoption of a given fate must be coupled to appropriate suppression of alternative fates. While much still remains to be understood about the nature of the molecular pathways involved in the regulation of stem and progenitor cell fate, it is generally accepted that transcription factors are key intrinsic regulators of these decisions, through modulation of overlapping or linked networks of transcription factors (Enver and Greaves, Cell; 94:9-12, 1998, Shivdasani and Orkin, Blood; 87:4025-4039, 1996, Rothenberg et al, Dev Biol; 246:29-44, 2002). Figure 1. We have used multiple genome-wide and gene-specific approaches to examine the molecular mechanisms that regulate gene expression and consequently cell fate in haemopoietic mulipotential progenitor cells and their more differentiated progeny. In parallel, we have explored how chimaeric transcription factors associated with leukaemia impact the transcriptional circuitry and behaviour of haemopoietic stem and progenitor cells.
Our studies of normal cell fate control have been underpinned by the generation of a data-resource containing gene expression and microRNA profiles, TF and histone ChIP data as well as perturbation data and functional readouts derived from murine multipotential progenitors undergoing self-renewal and differentiation. The resource is complemented by related datasets from mouse and human primary and leukaemic cells as well as embryonic stem cells. At a simple level this resource has underpinned gene discovery studies of novel regulators of stem and progenitor cell fate such as Nov/CCN3; an essential regulator of human cord blood derived stem cells (Gupta et al 2007), Cited -2; a stem regulator shared with ES cells (Kranc et al 2009) and MLLT3, a novel player in the erythroid lineage (Pina et al 2008). A greater challenge has been to assemble these and related regulators into transcriptional networks and model their behaviour (Enver et al 2009, Graf and Enver 2010). In this respect we have developed novel models of GATA-PU.1 interaction (Huang et al 2007, Chickarmane et al 2009) and are currently developing a stochastic model based on single cell molecular and behavioural analysis that affords inference of the rules of lineage commitment in the blood system. The concepts and approaches developed have applicability in other stem cell systems, most notably ESC, and have informed our attempts to develop systems level approaches to leukaemia (see below).
Our current work is cancer biology based on the premise that understanding the pathogenesis of malignancy requires knowledge of (i) the nature of the underlying mutations, (ii) the cellular compartments in which they arise and (iii) their functional impact and its dependence on cellular context. We are exploring these issues in the context of t(12;21) associated childhood ALL. In this paradigmatic disorder, the fusion oncogene TEL-AML1 that encodes a chimaeric transcription factor constitutes an initiating or ‘first hit’ mutation. The identities of common co-operating genes in this disease (eg TEL1 and Pax5) are known, and significant insights into the cellular hierarchies of the pre-leukaemic and leukaemic phases have been made. Using a combination of experimental modelling and detailed analysis of patient derived samples, we are examining the nature and functional impact of the transcriptional networks nucleated by TEL-AML1 in different cellular compartments and stages of the disease as well as their vulnerability to therapeutic interventions. Our work begins to extend the analysis of leukaemia to the systems biology level and the knowledge of cellular and molecular targets gained, will further provide a basis for informing novel therapeutic approaches. Key contributions in our programme on leukaemia have been the identification of the cellular targets in which the TEL-AML chimaera first has biological impact (Hong et al 2008, Figure 2) which established the concept of pre-leukaemic stem cells in humans and laid the foundation for a follow up collaborative study which has identified genetic heterogeneity in the stem cell compartment of childhood ALL (Andersen et al 2011). We are now developing these ideas in the settings of childhood AML and initiating a new programme of study in lymphoma led by Rajeev Gupta.