This project is one of 15 four year PhD Studentships funded by Medical Research Scotland (MRS) (https://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and External Partner Organisation (EPO). The Studentship will provide first-class research-training, and additional training provided by the EPO, needed to equip the successful candidate for a science career in an increasingly competitive market.
"Understanding the role of the immune system in paediatric blood cancer" to be delivered by the University of Edinburgh [Supervisors: Dr Samanta Mariani (Centre for Inflammation Research, University of Edinburgh) and Professor Katrin Ottersbach (MRC Centre for Regenerative Medicine, University of Edinburgh] and Macomics Ltd (https://macomics.com) [External Partner Organisation supervisor: Dr Carola Ries].
Infant leukaemia originates in utero and, even if rare, it is characterised by an aggressive clinical presentation in a very vulnerable host (infants <1 year). The majority of acute leukaemia in infants are characterised by chromosomal translocations of the Mixed Lineage Leukaemia (MLL1) gene. MLL-rearranged leukaemias are characterised by frequent relapses and poor prognosis. Intensification of chemotherapy may reduce the risk of relapse, but it causes therapy related morbidity and mortality, and late effects in survivors due to the indiscriminate killing of proliferating cells (representing the majority of the cells in a growing infant). There is the urgent need to further investigate the onset/early progression of the disease, to better understand its biology and create new knowledge that might help, in the future, develop new therapeutic strategies for the treatment of infant leukaemia.
In addition to cell intrinsic factors that regulate the proliferation/persistence of leukaemia stem cells, it has been shown that the leukaemia microenvironment plays a role in leukaemia progression/chemoresistance. Among the cells present in the leukaemia microenvironment, macrophages can become leukaemia associated macrophages and start helping the leukaemia cells instead of defending the host. Despite the evidence that macrophages can promote the disease progression in different types of adult leukaemia, their role in infant leukaemia has never been explored. It is the purpose of this project to explore the role of LAMs in infant leukemia, and find new targets to develop a novel LAM-targeting immunotherapy approach.
Hypothesis:
Embryonic macrophages become leukemia-associated macrophages (LAMs) during MLL-AF9+ infant leukaemia and promote cancer malignancy and/or chemoresistance.
Aim:
Investigate the role of LAMs in the onset/progression of MLL-AF9+ infant leukemia in mouse fetuses/pups, and find new targets to develop immunotherapy strategies for the disease.
Objectives:
1) Define the transcriptome of leukaemia stem cells and LAMs in MLL-AF9+ fetuses and newborn pups.
2) Identify the spatial distribution and the functions of the foetal liver and foetal bone marrow macrophages in response to leukemia onset/early progression.
3) Generate genetically modified human induced pluripotent stem cell (hiPSC)-derived macrophages to recreate the LAM phenotype in vitro and test their function.
Techniques:
Single cell RNAseq
Multi-colour flow cytometry
Cell culture (cell lines, primary cells and human iPSCs)
Molecular biology techniques (PCR, Real time PCR, western blotting)
Hands on animal work (mouse embryonic and adult tissue dissection)
ENQUIRIES:
Enquiries should be sent by email to Dr Samanta Mariani
[Email Address Removed]
APPLICATIONS:
Applicants must have obtained, or expect to obtain, a first or 2.1 UK honours degree and/or MSc with a Merit or Distinction, or equivalent for degrees obtained outside the UK, in a relevent biology, biomedical or biological sciences subject.
Applications are welcome from UK nationals, EU nationals that hold UK settled or pre-settled status and international students. Medical Research Scotland will fund fees at the Home (UK) rate. The University of Edinburgh will offer a scholarship to cover the difference between home and international fees for successful international applicants.
Applicants should
1) complete the online applicaiton form available here
and
2) should submit the following documents: (i) Personal statement about their research interests and their reasons for applying, (ii) a full Curriculum Vitae and (iii) ask two referees to submit their reference letters, by email to:
[Email Address Removed]
no later than 5pm on the closing date for applications.
Please note, your application may be shared with the funders of this PhD Studentship, Medical Research Scotland and Macomics Ltd.
Interviews are expected to take place 2-3 weeks after the closing date for applications.
It is anticipated that the PhD Studentship will start 2 October 2023.
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