UCL Cancer Institute


Project: Modelling childhood acute lymphoblastic leukaemia in induced pluripotent stem cells

11 July 2023

PhD studentship

Project: Modelling childhood acute lymphoblastic leukaemia in induced pluripotent stem cells

  • Primary supervisor: Professor Tariq Enver
  • Secondary supervisor: Dr Jason Wray

This is a 4-year studentship funded by a philanthropic donation, which covers tuition fees at the UK rate and a stipend of £23,000 per year. The start date for this studentship is October 2023. 

Closing date: Friday 18th August 2023


Introduction: B cell lymphoblastic leukaemia (B-ALL) is the commonest childhood cancer. In the UK some 550 children under the age of 16 are diagnosed annually. Although 70-80% survive, treatments are long and arduous; many survivors suffer long-term medical and psychological complications, their education is invariably disrupted and the impact on family relationships can be severe. The outlook for those who do not respond, or relapse is poor. Thus, there is a need to develop more effective, less toxic therapies.

Broad scientific aims: Important insights can be gained by understanding how childhood B-ALL arises. Although the precise mutational profile in each patient is unique, the range of mutations observed is small compared to other cancers, making experimental modelling tractable. Studying how leukaemogenic mutations collectively impact blood formation may uncover new drug targets and could inform strategies to prevent B-ALL.

Scientific background: Childhood B-ALL has foetal origins, it can be thought of as a developmental disorder - initiating (‘first-hit”) mutations occur in utero. Children with Down Syndrome have 30-fold increased risk of B-ALL, and trisomy 21 (T21) is considered a “first-hit” event in leukaemogenesis. The most frequent second-hit mutations in DS-ALL converge on the JAK/STAT signalling pathway, including up-regulation of the cytokine receptor, CRLF2, constitutive activation of the IL7-Receptor (IL7R) and activating mutations in JAK2. T21 is known to alter haematopoiesis, but how it collaborates with second hit events during leukaemogenesis is unclear. 1-2% of non-DS children are born carrying an initiating mutation associated with B-ALL (the commonest being the ETV6-RUNX1 fusion) in a small sub-population (clone) of their blood cells. We have identified a lympho-myeloid haematopoietic progenitor cell, unique to human foetal haematopoiesis, that is ‘trapped’ or blocked from differentiating by ETV6-RUNX1, and which for these reasons is a candidate cell-of-origin of childhood B-ALL. Having a ‘pre-leukaemic’ ETV6-RUNX1 lympho-myeloid clone has no clinical impact for most children; it becomes undetectable by adolescence and no leukaemia occurs. However, in 1% of cases, secondary mutations occur, leading to B-ALL (in contrast to DS these are commonly loss of the un-mutated ETV6, loss of PAX5 and loss of CDKN2A).

Experimental Strategies: Human induced pluripotent stem cells (IPSCs) can be induced to differentiate in vitro and faithfully recapitulate foetal definitive haematopoiesis, affording a ready source of lympho-myeloid haematopoietic progenitor cells for modelling initiating and downstream mutations in a biologically relevant cellular environment.

The student will use this system to model DS-ALL using isogenic IPSC lines di- or tri-somic for chromosome 21 to generate lympho-myeloid progenitors using established protocols for directed B-cell differentiation. These will be further engineered to carry common second-hit events associated with DS-ALL. CRISPR/Cas9 based strategies will be employed to modify the endogenous loci and precisely mimic the mutations that occur in DS-ALL, establishing a panel of isogenic IPSC lines representing stages of oncogenic transformation. Flow-cytometry and mass-cytometry will be used to simultaneously interrogate immuno-phenotype, cell cycle phase, apoptosis, and JAK/STAT signalling. This will be complemented by transcriptomic and epigenomic analyses of sorted cell fractions and, using single cell ‘multi-omic’ approaches to characterise cell states with high resolution and paint a detailed picture of the impact of T21 and second hit mutations on the differentiation trajectories as cells mature from progenitors to B-cells and associated changes to the epigenome.

Both DS and ETV6-RUNX1 reduce B-cell output, suggesting that their role in leukaemogenesis is to predispose cells of the B-lineage to additional transforming events. We will compare the data generated during this project to our existing flow-cytometry, mass-cytometry and RNA-seq data for the ETV6-RUNX1 system to explore possible commonalities in these alternative paths to transformation. This project will reveal the nature of the pre-leukaemic state established by T21 and allow us to infer the likely cell of first impact for subsequent transformation by second hits. Novel immuno-phenotypes associated with DS-ALL transformation facilitating prospective identification may be uncovered facilitating further study and with potential prognostic value. Pathways disrupted by T21, alone or in collaboration with secondary events, will be identified and may suggest therapeutic vulnerabilities. Moreover, by comparison to non-DS-ALL insights with implications across childhood B-ALL will be gained.

More detailed information about the research project is available on request from t.enver@ucl.ac.uk


The UCL Cancer Institute is a state-of-the-art institute to consolidate cancer research at UCL and promote links with our partner teaching hospitals, in order to support excellence in basic and translational studies. The Institute draws together talented scientists who are working together to translate research discoveries into developing kinder, more effective therapies for cancer patients. It is a Cancer Research UK and Experimental Cancer Medicine Centre, and contains approximately 580 staff, including 120 PhD and MD (Res) students and 40 MSc students. Core facilities within the Institute include: Genomics Facility (gene expression microarrays); Proteomics Facility; Imaging and Cell Sorting (confocal, time-lapsed microscopy, MoFlo FACS); Pathology Suite (laser capture microdissection, tissue arrays);

Experimental Imaging (with UCL Institute of Child Health); and Transgenesis. Further information on the Cancer Institute can be found at https://www.ucl.ac.uk/cancer.

Ideal person specification


  • Minimum upper second-class Honours Degree in an associated discipline, or an overseas qualification of an equivalent standard.
  • Knowledge of molecular and cell biology
  • Preliminary knowledge of research techniques.
  • Evidence of motivation for and understanding of the proposed area of study.
  • Ability to develop understanding of complex problems and apply in-depth knowledge to address them.
  • Potential to develop expertise in new areas of the subject.
  • Potential for innovation and initiative, and evidence of an ability to work independently.
  • Effective communication skills in both written and spoken English.


  • Relevant laboratory research experience.
  • Experience of basic tissue culture and molecular biology.

Students will also need to qualify as UK fee payers and meet UCL general admissions criteria.


Duties and responsibilities


  • To apply highly specialist scientific skills and expertise to lead in the delivery of high quality research and the preparation of high-impact research publications.
  • To keep abreast of current developments in this research area.
  • To report research progress to the supervisory team, the Cancer Institute, and at scientific conferences and meetings.
  • To work with other Scientists within the team as necessary
  • To work safely by adhering to all University policies and practices, including preparing and following laboratory risk assessments, and complying with Health and Safety policies, ethical approval processes and Human Tissue Act guidelines.

Analytical and Judgement Skills

  • To demonstrate a high-level of technical and analytical skill to resolve highly complex scenarios, requiring analysis, interpretation and expert judgement to find the most appropriate solutions.
  • To identify, interpret and integrate information from a wide variety of sources, and critically evaluate the quality and assumptions of these data.
  • To show initiative and the ability to make decisions in areas where no previous work has been undertaken.
  • To show awareness of your own developmental needs and undertake appropriate training where appropriate.
  • To comply with professional codes of conduct.
Application Procedure

To apply for this studentship, you must:

  1. Submit the following three documents.
    1. Your full CV including:
      1. The names and contact details of two referees (at least one of which must be an academic reference from your previous educational institution).
      2. And a short summary (<500 words) detailing how your experience and ability matches the project and the person specification.
    2. A single PDF file containing scans of your award certificate and transcripts showing your unit/module marks for all of your degrees, undergraduate and postgraduate. If any of your original documents are not in English you must submit an official English translation with them.
    3. An equal .

This form will be separated from your application before it is forwarded to shortlisters. By submitting this form you are giving us consent to use the data contained for quality and monitoring purposes. Data will be anonymised.

These three documents must be emailed to ci.scholarships@ucl.ac.uk by Friday 18th August 2023 , 17:00 (GMT).The subject line of your email should contain the studentship code “Enver23 and your surname.

  1. You must also contact your referees and ask them to submit their references by email to ci.scholarships@ucl.ac.uk from a verifiable academic or professional email address. The studentship code above and your surname must be in the email subject line.

References must be received from your referees by Friday 25th August 2023 ,17:00 (GMT). Please ensure that your referees have submitted references for you, as we will not chase missing references. Incomplete applications will not be forwarded to the Shortlisting Panel.

Shortlisting and notification will likely take place W/C 28th August 2023.

Queries about the application procedure or recruitment process should be directed to: ci.pgreducation@ucl.ac.uk