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Investigating the role of the microenvironment in paediatric and adult acute myeloid leukaemia


   Institute of Cancer Sciences

  Dr Karen Keeshan  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The incidence of acute myeloid leukaemia (AML) increases with age, and in childhood accounts for 20% of all leukaemia. The current overall survival rate in children is only 60-70%, and thereafter falls progressively with age to 5-15% in the elderly. Both children and adults die from a combination of relapse (up to 35% and 99% respectively) and treatment-related mortality during both induction and consolidation therapy. This highlights the critical need for novel paediatric- and adult-specific AML therapies. Whilst there are many biological similarities between paediatric and adult AML with continuum across the age range, it is accepted that many characteristics of leukaemia are associated with age of disease onset. These include chromosomal aberrations, gene mutations, and differentiation lineage. Consistent with this, work from my lab has shown that paediatric AML is biologically and molecularly different to adult AML, with the age of the cell of origin impacting leukaemia latency, lineage, niche and molecular profiles. Using RNA-sequencing we showed a specific transcriptional signature of young AML that distinguishes paediatric disease biology from adult. This was an important study published in Nature Communications in 2018 providing proof of concept that there are molecular features of paediatric AML distinct from adult AML (1, 2).

The age and microenvironment of the cell expressing the genetic driver plays a significant role in the initiation, phenotype and chemoresistance of the leukaemia. This has led to the hypothesis that the genomic state of the cell of origin and bone marrow (BM) stromal cells play significant roles in the pathogenic properties of paediatric and adult AML. Leukaemic cells depend on the BM niche, and not only co-opt normal niches but also alter them to their own advantage for propagation and treatment survival. It is not known whether changes that occur in the leukaemic BM niche are the same in paediatric and adult AML.

Overall, our goal is to understand and/or establish mechanisms relating to paediatric and adult acute myeloid leukaemia (AML), in order to determine better strategies to control or eliminate disease. We investigate the cell of origin, age-related features, and the role of the leukaemia stem cell and the bone marrow microenvironment in mechanisms of chemoresistance and disease relapse.

This project will investigate the role of the microenvironment in age-specific AML disease and will focus on genetically distinct subtypes of paediatric and adult using a number of models and approaches including: transgenic and transplantation transplantation (BMT) murine models: CRISPR/Cas9 gene editing approaches; bulk and single cell transcriptomic technologies; training in bioinformatics; murine and human stromal co-cultures; primary AML samples from paediatric and adult patients; will also employ flow cytometry, cellular and molecular biology technologies. This PhD studentship offers extensive dual training in both fundamental and translational biology of leukaemia, an environment encompassing clinical and basic researchers, and training opportunities as part of the college graduate program.

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References

1. Aung MMK, Mills ML, Bittencourt-Silvestre J, Keeshan K. Insights into the molecular profiles of adult and paediatric acute myeloid leukaemia. Mol Oncol. 2021 Jan 9. doi: 10.1002/1878-0261.12899. PMID: 33421304.
2. Chaudhury S, O'Connor C, Canete A, Bittencourt-Silvestre J, Sarrou E, Prendergast A, et al. Age-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias. Nat Commun. 2018;9(1):5280.
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