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Haematopoietic Stem Cell Biology: Understanding how the normal haematopoietic stem/progenitor hierarchy is disrupted during the development of myeloid malignancies

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  • Full or part time
    Dr A Mead
    Dr Supat Thongjuea
    Dr Bethan Psalia
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Understanding how the normal haematopoietic stem/progenitor hierarchy is disrupted during the development of myeloid malignancies. Our overarching aim is to improve the management of myeloproliferative neoplasms and related conditions through better monitoring and therapeutic targeting of malignant stem cell populations.

The Haematopoietic Stem Cell Biology (HSCB) Laboratory is focused on understanding how the normal haematopoietic stem/progenitor hierarchy is disrupted during the development of myeloid malignancies. Our overarching aim is to improve the management of myeloproliferative neoplasms and related conditions through better monitoring and therapeutic targeting of malignant stem cell populations.

In order to achieve this, we are applying a number of approaches:

1. Development of genetically engineered models of haematopoietic malignancies e.g. Booth et al, Cancer Cell, 2018

2. Single cell analysis of leukaemia stem cells e.g. Giustacchini et al, Nature Medicine, 2017

3. Characterisation of cell-extrinsic regulators of haematopoietic stem/progenitor cells, including bone marrow niche populations e.g. Mead et al, Journal of Experimental Medicine, 2017

We will be offering projects focused on single cell analysis of normal and malignant haematopoietic stem cell populations. Specifically, we would like to combine molecular barcoding approaches with single cell RNA-sequencing in order to gain insights into lineage fate in normal haematopoiesis and how this is disrupted during the development of myeloid malignancies. Using such approaches, we have already identified multiple novel candidate regulators of haematopoiesis that will need to be functionally validated using genome editing approaches, in particular focusing on certain intrinsic and extrinsic regulators of normal haematopoietic stem cells and how these become disrupted during the development of a severe bone marrow cancer called myelofibrosis.

The studentship will provide an excellent training in the exciting emerging field of single cell analysis using state of the art molecular and stem cell biology approaches. We have established protocols for single cell genomics, stem cell assays, bioinformatics analysis and genome editing. Students in the Mead laboratory will be paried up with an experienced researcher and will meet with their supervisor on a weekly basis to discuss their project.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold 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.


Funding Notes

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

References

Booth CAG, Barkas N+, Neo WH+, Boukarabila H, Soilleux EJ, Giotopoulos G, Farnoud N, Giustacchini A, Ashley N, Carrelha J, Jamieson L, Atkinson D, Bouriez-Jones T, Prinjha RK, Milne TA, Teachey DT, Papaemmanuil E, Huntly BJP, Jacobsen SEW*, Mead AJ*à. Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors. Cancer Cell. 2018;33(2):274-91 e8.+,* Equal contribution. àLead corresponding author


Giustacchini A+, Thongjuea S+, Barkas N, Woll PS, Povinelli BJ, Booth CAG, Sopp P, Norfo R, Rodriguez-Meira A, Ashley N, Jamieson L, Vyas P, Anderson K, Segerstolpe A, Qian H, Olsson-Stromberg U, Mustjoki S, Sandberg R, Jacobsen SEW*, Mead AJ*. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med. 2017;23(6):692-702. +,* Equal contribution.


Mead AJ, Neo WH, Barkas N, Matsuoka S, Giustacchini A, Facchini R, Thongjuea S, Jamieson L, Booth CAG, Fordham N, Di Genua C, Atkinson D, Chowdhury O, Repapi E, Gray N, Kharazi S, Clark SA, Bouriez T, Woll P, Suda T, Nerlov C, Jacobsen SEW. Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation. J Exp Med. 2017;214(7):2005-21.


Mead AJ, Mullally A. Myeloproliferative neoplasm stem cells. Blood. 2017;129(12):1607-16.


Psaila B, Barkas N+, Iskander D+, Roy A, Anderson S, Ashley N, Caputo VS, Lichtenberg J, Loaiza S, Bodine DM, Karadimitris A, Mead AJ*, Roberts I*. Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways. Genome Biol. 2016;17:83.. +,* Equal contribution.


Povinelli BJ, Rodriguez-Meira A, Mead AJ. Single cell analysis of normal and leukemic hematopoiesis. Mol Aspects Med. 2018;59:85-94.

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FTE Category A staff submitted: 238.51

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