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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.

Mead

About the Research

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.

 

Training Opportunities

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.

 

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.

 

Publications

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.

Supervisors