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Normal and Leukaemic Blood Stem/Progenitor Cell Biology


Project Description

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).

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:
1. Dissection of 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.
2. Study of 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.
3. Definition of 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.
4. 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.
5. 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. 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.
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.


Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2020 entry, the application deadline is 10th January 2020 at 12 noon (midday).
Please visit our website for more information on how to apply.

References

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 doi: 10.1016/j.ccell.2019.06.007 (2019). PMID: 31303423.

Quek L, David M, Kennedy A, Metzner M, Amatangelo M, Shih A, Stoilova B, Quivoron C, Heiblig M, Willekens C, Saada V, Peniket A, Bernard O, Agresta S, Yen K, MacBeth K, Stein E, Levine R, De Botton S, Thakurta A, Penard-Lacronique V and Vyas P. Clonal Heterogeneity in Differentiation Response and Resistance to the IDH2 inhibitor Enasidenib in Acute Myeloid Leukemia. Nature Medicine 24:p1167-1177 (2018). PMID: 30013198.

Karamitros D, Stoilova B, Aboukhalil Z, Hamey F, Reinisch A, Samitsch M, Quek L, Otoo G, Repapi E, Doondeea J, Usukhbayar B, Calvo J, Taylor S, Goardon N, Six E, Pflumio F, Porcher C, Majeti R, Gottgens B, Vyas P. Functional and transcriptional heterogeneity of human hemopoietic lympho-myeloid progenitors at the single cell level. Nature Immunology. 19:p85-97 (2018). PMID: 29167569.

Quek L, Otto GW, Garnett C, Lhermitte L, Lau I, Karamitros D, Doondeea J, Usukhbayar B, Goardon N, Ivey A, Gu Y, Gale R, Davies B, Sternberg A, Killick S, Hunter H, Cahalin P, Price A, Carr A, Griffiths M, Virgo P, Mackinnon S, Hills R, Grimwade D, Freeman S, Burnett A, Russell N, Craddock C, Mead AJ, Peniket A, Porcher C & Vyas P. Functional and genetic heterogeneity of distinctive leukemic stem cell populations in CD34- human acute myeloid leukaemia. Journal of Experimental Medicine 213(8)1513-1535 (2016). PMID: 27377587.


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FTE Category A staff submitted: 238.51

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