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Unravelling mechanisms of disease progression in Myeloproliferative Neoplasms


   Weatherall Institute of Molecular Medicine

   Friday, December 03, 2021  Competition Funded PhD Project (Students Worldwide)

Oxford United Kingdom Cancer Biology Cell Biology Genomics Molecular Biology Molecular Genetics Medicine

About the Project

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.

The major focus of our research programme is to identify and genetically model leukaemic and pre-leukaemic stem cells in myeloid malignancies. Our overarching aim is to better characterise the cellular and molecular biology of these key populations of cells in order to understand how malignant stem cell populations might be more effectively targeted and eradicated. In order to achieve this, we are applying a number of approaches:  

1. Development of genetically engineered models of myeloid malignancies in order to study the impact of specific driver mutation(s) on the establishment, evolution and propagation of leukaemic stem cells. These models provide an ideal platform for in vivo pre-clinical development of novel therapies.  

2. Analysis of leukaemia stem cells in patients with chronic myeloid leukaemia, myeloproliferative neoplasms, juvenile myelomonocytic leukaemia and related conditions. We have developed new methods to study the molecular signatures of normal and malignant stem cell populations at the single-cell level. This is crucial in order to unravel the intratumoural heterogeneity within any phenotypically defined malignant stem cell population. We are also applying this approach to analyse patients receiving novel targeted therapies in order to better understand mechanisms of resistance to molecularly targeted therapy in stem cell populations and pathways of transformation to more aggressive forms of disease.  

3. Identification of somatic and germline genetic abnormalities associated with the development of myeloid malignancies. Our particular focus is to refine risk stratification of patients using these molecular markers and also to gain a better understanding of how germline mutations might disrupt stem/progenitor cell populations to promote the development of myeloid malignancies.  

4. Characterisation of cell-extrinsic regulators of haematopoietic stem/progenitor cells, including bone marrow niche populations, and how they are disrupted during the development of myeloproliferative neoplasms and related conditions.

This specific project is focused on mechanisms of disease progression in myeloproliferative neoplasms. In the first part of the project, the student will analyse samples from a cohort of patients with myeloproliferative neoplasms whose disease has progressed to acute myeloid leukaemia. This will provide an excellent training in cutting edge single cell genomics techniques. In the second part of the project, the student will learn bioinformatics approaches to analyse the data. In the third part of the project the student will use these data to identify potential candidate genes which are aberrantly expressed and might contribute functionally to the disease progression. The mechanistic function of these genes will be explored using functional assays, providing a training in stem cell assays and genome engineering.

The Mead laboratory leads on single-cell research at the WIMM and the student will gain a state of the art training in this exciting field. Prof Mead maintains close links with the clinical NHS haematology department in Oxford, key to obtain patient samples and enable the translation of scientific research into clinical practice. Previous students in the Mead Laboratory have conducted highly successful DPhils. For example, Christopher Booth (completed Jan 2018) was awarded the Ita Askonas Medal for best DPhil student presentation at the WIMM day in 2016, the RDM Graduate Prize in 2018 and published a first author paper in Cancer Cell. Alba Rodriguez-Meira (year 4 DPhil student in the Mead Lab) developed TARGET-seq, was awarded the Ita Askonas Medal for best DPhil student presentation in 2018 and has a paper in Molecular Cell in year 3 of her studies.

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.


Funding Notes

Funding for this project is available to scientists through the WIMM Prize Studentship and the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all fees paid and will receive a stipend.

For October 2022 entry, the application deadline is 3rd January 2021 at 12 noon midday, UK time.

Please visit our website for more information on how to apply.



References

Louka E*, Povinelli B*, Rodriguez-Meira A, Buck G, Wen WX, Wang G, Sousos N, Ashley N, Hamblin A, Booth CAG, Roy A, Elliott N, Iskander D, de la Fuente J, Fordham N, O'Byrne S, Inglott S, Norfo R, Salio M, Thongjuea S, Rao A, Roberts I+, Mead AJ+. Heterogeneous disease-propagating stem cells in juvenile myelomonocytic leukemia. J Exp Med. 2021;218(2). +,* Equal contribution. Cover image and featured article with commentary ‘Stem cell origins of JMML’.
Psaila B*, Wang G*, Rodriguez-Meira A, Li R, Heuston EF, Murphy L, Yee D, Hitchcock IS, Sousos N, O'Sullivan J, Anderson S, Senis YA, Weinberg OK, Calicchio ML, Center NIHIS, Iskander D, Royston D, Milojkovic D, Roberts I, Bodine DM, Thongjuea S, Mead AJ. Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets. Mol Cell. 2020;78(3):477-92 e8. *Equal contribution.
Rodriguez-Meira A, Buck G, Clark SA, Povinelli BJ, Alcolea V, Louka E, McGowan S, Hamblin A, Sousos N, Barkas N, Giustacchini A, Psaila B, Jacobsen SEW, Thongjuea S, Mead AJ. Unravelling Intratumoral Heterogeneity through High-Sensitivity Single-Cell Mutational Analysis and Parallel RNA Sequencing. Mol Cell. 2019;73(6):1292-305 e8. Cover image and featured article.
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*. Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors. Cancer Cell. 2018;33(2):274-91 e8.+,* Equal contribution. Lead corresponding author
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. Featured article.
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. Cover image and featured article.
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.

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