Vyas Group - Normal and Leukaemic Blood Stem/Progenitor Cell Biology
Understanding the fundamental biological processes underlying normal and malignant haematopoiesis and translate this to improve patient outcomes through new rational therapies.
About the Research
Our laboratory studies the mechanisms regulating normal blood stem and progenitor cell differentiation and how these are perturbed in blood cancers such as Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS). Our aim is to not only to understand fundamental biological principles about cell fate choice and differentiation and how they are corrupted in disease, but also to improve therapies for patients. We combine molecular and cellular studies on primary normal and leukaemic human blood stem/progenitor cells with studies in appropriate models. We use state-of the art genetic screens, transcriptional, epigenetic and immunological assays on highly purified cells and single cells. The PhD projects in our laboratory will provide a strong foundation in stem cell and cancer biology using leukaemia as a model, and in immunology and training in cellular, molecular and computational analyses with a focus on single cell methods.
Blood cell differentiation is one of the best characterised models to study how normal tissue-specific stem cells give rise to diverse cell types. When the complex regulatory mechanisms controlling this process are corrupted it can give rise to blood cell cancers, like leukaemia. The most common aggressive adult human blood cell cancer AML. It is often preceded by a pre-leukaemic condition called MDS. Many of the recurrent genetic mutations that cause AML and MDS perturb early blood stem/progenitor differentiation to give rise initially to pre-leukaemic stem cells (Pre-L SC). Pre-L SC then acquire additional changes that transform them to leukaemic stem cells (LSCs).
Our laboratory has five main areas of research and PhD projects are available in all five areas:
- There is a state-of the art project to dissect the detailed molecular mechanisms that regulate the transition of normal human blood stem through to early lympho-myeloid progenitors, especially as they make the key decisions to make either myeloid or lymphoid cells. The mechanisms that regulate these processes are often corrupted by common recurrent mutations that give rise to Pre-L SC and LSCs.
- We are embarking a on a novel project to study the interaction of germline variation and somatic variation to define how Pre-L SC clone size varies and how that determines the progression of Pre-LSC to LSCs. This project will involve both functional, computational and statistical approaches.
- We have a novel project to define cellular components and critical signalling pathways in the normal stem/progenitor niche as a prelude to understanding how the two-way communication between the niche and stem/progenitor cells is altered when normal stem/progenitor cells are transformed into Pre-L SC and LSCs.
- In both AML and MDS the role of the immune system in controlling Pre-L SC and LSC remains relatively under-explored yet it is clear that immune responses control and eradicate Pre-L SC and LSCs when patients receive an allogeneic transplant – through a process called graft versus leukaemia (GvL). We have an exciting project to characterise the biology of GvL and how AML evades GvL in some patients.
- Our laboratory intensively studies sequential bone marrow and blood samples from AML and MDS patients receiving state of the art therapies to understand the clonal basis of response and resistance. We have an innovative PhD project focussed on studies dissecting mechanisms by which novel targeted therapies work, and fail, in patients. These studies are vital to improve survival, and clinical benefit, for AML and MDS patients.
PhD students in the Vyas laboratory receive in depth training in studying normal stem/progenitor cells, Pre-L SC and LSCs.
The key methods in doing this include:
- Complex multi-colour flow cytometric analysis and sorting, including index sorting and single cell sorting. All students will be able to independently use flow analysers and sorters.
- Complex in vitro and in vivo assays of normal and leukaemic stem/progenitor cell function including single cell assays.
- Use of CRISP gene-editing in primary human cells at specific loci (including addition of specific markers) and use of CRISPR genetic screens.
- Making next generation sequencing libraries for RNA-seq and ATAC-seq in single cells and in highly purified cell populations. Using methods to combine analysis of large number of cell-surface markers, the transcriptome (RNA-seq) and DNA for mutations and copy number variants in single cells (Cite-Seq, Target Seq, GOT). ChiP-Seq, Hi-C and Capture C to analyse chromatin structure and conformation.
- Intensive computational and statistical training (in R and Python) to analyse next generation sequencing data from “omic analyses” and genome-wide variant data.
- Use of appropriate models to study cell and gene function.
- Assays of T cell and innate immune cell function.
- Use of lentiviral bar-coding approaches to study cell fate.
In all methods PhD students will receive training and supervision from existing members of the laboratory in conjunction with managers of the WIMM core facilities. Computational training is provided through a dedicated 4-month full time course, on-line courses and one to one supervision and mentorship.
All students will have one to one supervision with Professor Vyas and the opportunity to present data and concepts from their project at the Vyas Lab meeting, and a separate journal club.
Critical components of training include: (i) learning how to dissect published paper; (ii) learning how to ask important questions; (iii) designing well-controlled experiments; (iv) not being afraid of getting things wrong; (v) learning to take ownership and control of the project; (vi) learning to write a thesis and scientific publications.
Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.
All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.
- Labuhn M, Perkins K, Papaemmanuil E, Matzk S, Varghese L, Amstislavskiy V, Risch T, Garnett C, Hernandez, D, Metzner M, Kenndy, A, Iotchkova V, Stoilova, B, Scheer C, Yoshida K, Schwarzer A, Taub J, Crispino JD., Weiss MJ, Hayashi A, Taga T, Ito E, Ogawa S, Reinhardt D, Yaspo ML, Campbell PJ, Roberts I, Constantinescu S, Vyas P, Heckl, D, Klusmann JH. (Joint last authors in bold). Mechanisms Of Progression Of Myeloid Preleukemia To Transformed Myeloid Leukemia In Children With Down Syndrome. Cancer Cell. 36 p123-138
- Quek, L., M.D. David, A. Kennedy, M. Metzner, M. Amatangelo, A. Shih, B. Stoilova, C. Quivoron, M. Heiblig, C. Willekens, V. Saada, S. Alsafadi, M.S. Vijayabaskar, A. Peniket, O.A. Bernard, S. Agresta, K. Yen, K. MacBeth, E. Stein, G.S. Vassiliou, R. Levine, S. De Botton, A. Thakurta, V. Penard-Lacronique, and P. Vyas, Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat Med, 2018. 24(8): p. 1167-1177.
- Karamitros, D., B. Stoilova, Z. Aboukhalil, F. Hamey, A. Reinisch, M. Samitsch, L. Quek, O. G., E. Repapi, J. Doondeea, B. Usukhbayar, J. Calvo, S. Taylor, N. Goardon, E. Six, F. Pflumio, C. Porcher, R. Majeti, B. Gottgens, and P. Vyas, Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells. Nature Immunology, 2018. 19: p. 85-97.
- Quek, L., G.W. Otto, C. Garnett, L. Lhermitte, D. Karamitros, B. Stoilova, I.J. Lau, J. Doondeea, B. Usukhbayar, A. Kennedy, M. Metzner, N. Goardon, A. Ivey, C. Allen, R. Gale, B. Davies, A. Sternberg, S. Killick, H. Hunter, P. Cahalin, A. Price, A. Carr, M. Griffiths, P. Virgo, S. Mackinnon, D. Grimwade, S. Freeman, N. Russell, C. Craddock, A. Mead, A. Peniket, C. Porcher, and P. Vyas, Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage. J Exp Med, 2016. 213(8): p. 1513-35.
- Goardon, N., E. Marchi, A. Atzberger, L. Quek, A. Schuh, S. Soneji, P. Woll, A. Mead, K.A. Alford, R. Rout, S. Chaudhury, A. Gilkes, S. Knapper, K. Beldjord, S. Begum, S. Rose, N. Geddes, M. Griffiths, G. Standen, A. Sternberg, J. Cavenagh, H. Hunter, D. Bowen, S. Killick, L. Robinson, A. Price, E. Macintyre, P. Virgo, A. Burnett, C. Craddock, T. Enver, S.E. Jacobsen, C. Porcher, and P. Vyas, Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell, 2011. 19(1): p. 138-52.
- Amatangelo MD, Quek L, Shih A, Stein EM, Roshal M, David MD, Marteyn B, Rahnamay Farnoud N, de Botton S, Bernard OA, Wu B, Yen KE, Tallman MS, Papaemmanuil E, Penard-Lacronique V, Thakurta A, Vyas P*, Levine RL*. * Joint last author. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130:732-741 (2017).