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Modelling of functional and tumour heterogeneity in human AML arisen from different cells-of-origin

Acute myeloid leukemia (AML) together with acute lymphoid leukemia (ALL) account for about one third of all paediatric cancers.

Applications are now closed for the 2019 postgraduate training programme.

  • Primary Supervisor: Prof Eric So, School of Cancer and Pharmaceutical Sciences, King’s College London
  • Secondary Supervisor: Prof Adrian Thrasher, Infection, Immunity, Inflammation Programme, UCL

Funding note: Non-EU candidates are not eligible to apply

Background

In contrast to childhood ALL, which has a relatively favourable prognosis, AML has a much poorer projection and is one of the deadliest cancers. AML maintained by a small fraction of cancer stem cells is frequently initiated and driven by mutations affecting transcriptional and epigenetic machinery[1].  While hematopoietic stem cells (HSCs) have been traditionally viewed as the origins of human leukemia, we and others have previously shown that mutated transcription factors can also confer self-renewal properties to otherwise short-lived myeloid progenitors to initiate AML in mouse models[2].  Importantly, these genetically and immunophenotypically identical AML exhibit different biology and responses to treatments, revealing an additional level of tumour heterogeneity originating from their cells-of-origin[3]. Although most of the current evidence and literature are based on mouse cell models, we recently demonstrate for the first time that both human HSCs and myeloid progenitors can indeed be transformed by MLL-fusions to induce phenotypically indistinguishable AML commonly found in both childhood and adult leukemia patients, confirming the clinical relevance of cancer cell heterogeneity arising from their cells-of-origin in genetically and immunophenotypically homogeneous populations. 

Project description

In this PhD project, we seek to provide new insights into this issue by using adeno-associated viral (AAVs) vectors in combination with CRISPR-CAS9 genome editing approach to recreate some of the most commonly AML mutations in human HSCs and early progenitors.  Establishing these models will enable us to prospectively identify the potential origins of the AML stem cells and characterize the transcriptional and epigenetic landscapes of the transformed cells leading to the observed cellular heterogeneity.  This cross-disciplinary project will take the full advantage of the expertise and support of complementing research groups within the newly form City of London CRUK Center. The team includes Prof. So’s group in KCL who pioneered modelling human AML and characterizing their aberrant epigenetic networks[1-3]; Prof. Thrasher’s group in UCL who has a long standing interest and track record in applying genome editing technologies in human haematopoietic stem and progenitor cells[4]; Dr Liswoski’s group in Children Medical Research Institute (CMRI) Sydney/UCL who specializes in developing novel AAV vectors for effective gene transfer and genome editing in HSCs [5]; and Prof. Ciccarelli’s group In the Crick/KCL who is an expert in cancer genomics and bioinformatics.

The successful student is expected to be exposed and receive training in all these areas during the PhD. The first-year rotations will include studies in So’s group, Thrasher’s group and Ciccarelli’s group.  In addition, the student will also have an opportunity to receive training on novel vector development at CMRI.  The candidate should have a minimum of BSc but preferably a MSc in one of these subjects (Biomedical Sciences; Biological Sciences; Biotechnology; Biochemistry; or related subjects).  Prior work experiences in a research lab or industry will be considered favourably.

Suitable candidates for this project will have degree in Biomedical / Biological Sciences or related subjects.

Potential research placements: 

  1. Leukemia and Stem Cell Biology: training on cancer biology and epigenetics. Prof So, King’s College London. 
  2. Molecular and Cellular Immunology: training on gene transfer/genome editing technology in HSPCs and molecular immunology. Prof. Thrasher, UCL. 
  3. Cancer Bioinformatics: bio-informatic and computational training on cancer genetics and epigenetics. Prof Ciccarelli, the Crick.

References

  1. Zeisig BB et al. SnapShot: Acute myeloid leukemia. Cancer Cell, 2012; 22(5): p. 698-698 e1.
  2. So CW et al. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell, 2003; 3(2): p. 161-71. Siriboonpiputtana T et al. Transcriptional memory of cells of origin overrides beta-catenin requirement of MLL cancer stem cells. EMBO J, 2017; 36(21): p. 3139-3155.
  3. Booth C, Gaspar HB, Thrasher AJ. Treating Immunodeficiency through HSC Gene Therapy. Trends Mol Med, 2016; 22(4): p. 317-327.
  4. Lisowski L, Tay SS, Alexander IE. Adeno-associated virus serotypes for gene therapeutics. Curr Opin Pharmacol, 2015; 24: p. 59-67.