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The Wilkinson group focuses on the biology and translational applications of blood-forming haematopoietic stem cells (HSCs). In cancer evolution and its therapy, HSCs may play the part of the villain or the hero. As a long-lived stem cell population, HSCs gradually accumulate genetic mutations and are therefore thought to be a cell-of-origin for several haematological malignancies. This has recently been strikingly seen in the clinical observation of Clonal Haematopoiesis of Indeterminate Potential (CHIP), where the peripheral blood cells become increasingly derived from a single HSC clone. CHIP is considered a pre-malignant state because it increases the risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and it is also a major risk factor for therapy-related myeloid malignancies. The genetics of this pre-malignant state are now well characterized, however, the cellular and molecular mechanisms are still incompletely understood.

Ex vivo haematopoietic stem cell expansion graphic

ABOUT THE RESEARCH

Contrasting this role in blood cancer evolution, healthy HSCs are also an important cellular therapy in the cancer treatment known as HSC (or bone marrow) transplantation. Through their ability for self-renewal and multipotency, HSCs can entirely reconstitute the haematopoietic system following transplantation. HSC transplantation currently represents the only curative treatment option for a number of haematological malignancies. However, the availability of suitable donor HSCs is a major bottleneck in the use of this therapeutic option. Additionally, current HSC transplantation paradigms are associated with a number of potentially serious side-effects meaning that it is considered a high-risk treatment option.

DPhil projects will aim to answer important biological questions about the genetics of healthy and malignant HSCs, or aim to develop novel HSC-based therapies. Projects will build on recently established methods to expand and edit transplantable HSCs long-term ex vivo (Wilkinson et al., Nature 2019; Wilkinson et al., Nature Communications 2021). We are looking for enthusiastic students to build our team working on:

  1. Characterising ex vivo self-renewing HSCs at the molecular and genetic levels
  2. Interrogating pre-malignant HSCs and their leukaemic transformation
  3. Developing novel HSC gene editing and transplantation technologies
  4. Establishing and characterising long-term ex vivo human HSC expansion cultures

Informal enquiries are welcome and can be directed to Adam Wilkinson (adam.wilkinson@imm.ox.ac.uk)

TRAINING OPPORTUNITIES

Training in haematopoietic stem cell biology and experimental haematology available. This may include ex vivo HSC expansion methodologies, in vivo transplantation assays and leukaemia models, CRISPR/Cas9 genome engineering, large-scale genetic screening, genomic approaches (RNA-seq, ATAC-seq, ChIP-seq), single cell assays, flow cytometry and fluorescence activated cell sorting (FACS), molecular cloning, and mouse modelling. Opportunities to work with collaborators in Oxford and elsewhere (UK, Japan, USA) available.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine 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.

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.

PUBLICATIONS

1

Wilkinson AC, Ishida R, Kikuchi M, Sudo K, Morita M, Crisostomo RV, Yamamoto R, Loh KM, Nakamura Y, Watanabe M, Nakauchi H, Yamazaki S. Long-term ex vivo hematopoietic-stem-cell expansion allows nonconditioned transplantation. Nature 2019. 571(7763):117-121.

2

Wilkinson AC, Dever DP, Baik R, Camarena J, Hsu I, Charlesworth CT, Morita C, Nakauchi

H, Porteus MH. (2021) Cas9-AAV6 gene correction of beta-globin in autologous HSCs

improves sickle cell disease erythropoiesis in mice. Nature Communications 12(1):686

3

Wilkinson AC, Ishida R, Nakauchi H, Yamazaki S. Long-term ex vivo expansion of mouse hematopoietic stem cells. Nature Protocols 2020. 15(2):628-648.

4

Nishimura T, Hsu I, Martinez-Krams DC, Nakauchi Y, Majeti R Yamazaki S, Nakauchi H, Wilkinson AC. Use of polyvinyl alcohol for CAR T cell expansion. Experimental Hematology 2019. 80:16-20.

5

Wilkinson AC, Igarashi KJ, Nakauchi H. Haematopoietic stem cell self-renewal in vivo and ex vivo. Nature Reviews Genetics. 2020; 21(9):541-554.