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Origins of chALL

About the Research

Leukaemia is the commonest childhood cancer and occurs when blood formation (haematopoiesis) is perturbed because of a genetic/molecular abnormality in haematopoietic stem and progenitor cells (HSPC). Human haematopoiesis is a dynamic process that starts in utero at 2-3 post-conception weeks (pcw) becoming established sequentially in the yolk sac, aorto-gonado-mesonephros (AGM), fetal liver (FL), and finally fetal bone marrow (FBM), which becomes the dominant haematopoietic organ at birth and remains so throughout postnatal life. Determining the characteristics and regulators of site- and stage-specific variation in haematopoiesis is key to understanding childhood blood disorders that originate before birth. We have used functional and molecular approaches including single cell assays to explore normal and abnormal haematopoiesis through the human lifetime.

Significantly all infant leukaemia and much of childhood acute lymphoblastic leukaemia (ALL) originate before birth, and this makes it important to understand fetal-specific B-cell development in humans and how it differs from postnatal B lymphopoiesis. This has been a key focus in the Roy lab, and we have mapped the human fetal B-cell developmental hierarchy for the first time, including the identification of fetal specific lymphoid progenitors that are absent in postnatal life.

The developmental stage-specific cellular and molecular characteristics of fetal and postnatal progenitors are likely to determine the biology of ALL at different ages. We are particularly interested in high-risk childhood ALL, such as infant ALL and Down syndrome associated ALL. We have recently developed a novel MLL-AF4+ infant ALL model using primary human HSPC. 

To establish whether differences in the transformability of cells or the cell of origin in fetal/postnatal life leads to specific, ontogeny-related leukaemia biology at different ages, we aim to develop models of high-risk childhood leukaemia in addition to MLL-AF4 ALL by transforming fetal and postnatal (paediatric and adult) HSPC using CRISPR based approaches. This will enable us to unravel the mechanisms that initiate and maintain poor prognosis disease, thereby allowing us to understand heterogeneity in patient outcomes. 

The identification of key developmental stage- or leukaemia-specific mechanisms will allow these to be targeted for treatment. We have begun to investigate some of our findings in target discovery and translational research projects, including novel immunotherapy.

The overarching aim of our research is to improve the outcomes of children with high-risk ALL using these strategies.

The main opportunities for DPhil students would be in these areas:

1) Developing faithful models of high-risk childhood ALL to better understand leukaemia initiation and maintenance at different ages

2) Mechanistic studies to understand key drivers of childhood ALL

3) Target discovery and translation of findings from (1) and (2) into preclinical studies

4) Hybrid wet lab/computational projects using multi-omics to understand how cell intrinsic and/or microenvironmental characteristics of the developmental stage at which a leukaemia originates, drives the biology of leukaemia at different ages (an appropriate computational biology co-supervisor will be appointed)

 Training Opportunities 

We work in close collaboration with other labs within the department and beyond. The Roy lab has longstanding expertise in working with rare primary human fetal tissues; including detailed functional assays using small cell numbers, and generating childhood leukaemia models using CRISPR-Cas9 gene editing. The student will be supported by experienced postdoctoral researchers in our lab, as well as collaborating labs to learn cutting edge functional/molecular techniques such as in vitro assays, flow cytometry, ChIP-sequencing, CRISPR-Cas9 gene editing, RNA sequencing/ATAC sequencing, single-cell transcriptomics/functional assays, and bioinformatics. All of these techniques are already in use in our labs; and additional training opportunities will be available for FACS sorting and computational analysis. There may also be opportunities to work on novel immunotherapies with our collaborators.

Students are encouraged to attend 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

O’Byrne et al, Blood 2019 (https://pubmed.ncbi.nlm.nih.gov/31383639/)

2

Popescu et al, Nature 2019 (https://pubmed.ncbi.nlm.nih.gov/31597962/)

3

Godfrey et al, Leukemia 2021 (https://pubmed.ncbi.nlm.nih.gov/32242051/)

4

Roy et al, 2021 in press (https://www.biorxiv.org/content/10.1101/2021.04.20.440420v1)

5

Jardine et al, 2021 in press (https://www.biorxiv.org/content/10.1101/2021.06.25.449771v1)

6

Rice et al (https://www.biorxiv.org/content/10.1101/2020.11.15.379990v2)