Niche determinants required for leukaemic and normal stem cell function

Supervisor:  Prof Paresh Vyas, Prof Claus Nerlov and Dr Andrew Smith

Post-natal haemopoiesis occurs in a complex specialised tissue, the bone marrow. The marrow is geographical compartmentalised with specific niches supporting the survival, differentiation and proliferation of the distinct haemopoietic stem and progenitor cell populations. These niches are poorly characterised for both normal and leukaemic human haemopoiesis. Understanding the cellular components of the niche and the critical molecules mediating niche-stem/progenitor cell interactions is vital to understand how these populations are sustained and give rise to both normal haemopoiesis and leukaemia.

Working with Prof C Nerlov, Prof Carr and Dr A Smith in the MRC Molecular Haematology Unit and the Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, we are building the tools to study niche composition and the requirement of different niche cell types for murine and human normal and leukaemic stem cells in mouse models that recreate the human niche in a variety of ways and compare it with the murine niche.

In this project the candidate will specifically test the role of the cell surface receptor CKIT (CD117) for the stem cell cytokine Stem Cell factor (SCF) also known as CKIT ligand in propagation of AML LSCs. We have shown that AML LSC express CD117 and this enriches for LSCs[1]. CKIT is required for normal stem cell function[2]. The candidate will now test its requirement for AML LSCs. The candidate will characterise the expression of CKIT in the niche and use CRISPR/Cas gene editing to establish the requirement of CKIT-KITL for AML LSC function.

In addition to this the candidate will work with the teams to optimise engineered scaffolds to study the optimal requirements for a niche for AML LSCs. This work will be complementary with efforts identifying the optimal normal haemopoietic stem cell niche. Elextrospun scaffolds will be made by the Carr Laboratory and the niche stromal cell requirements will tested by the Vyas Lab. We will work closely with the Nerlov laboratory that has been instrumental in imaging the niche[3] and with Dr Smith that has been developing new in vivo models to test LSC and HSC function.

Training Opportunities:

The project: This project will provide a comprehensive training in functional normal and leukaemic stem cell biology, stromal biology, using powerful in vivo approaches, high-definition imaging, flow cytometry, molecular biology, gene editing, computational biology and biochemistry.

The environment: The Vyas laboratory is based in the MRC Molecular Haematology Unit (MHU), MRC Weatherall Institute of Molecular Medicine (WIMM) (www.imm.ox.ac.uk). There is a world-class FACS facility, state of the art imaging, xenograft experiments are routine, high-class bioinformatic support and open access to the genomics core.

Formal Training:

Informal Training

Presentation

Academic activities

MHU and WIMM have separate weekly international/national speaker seminar series.

Scientific Themes:      Developmental Biology & Stem Cells, Haematology

References:

  1. Quek L, Otto GW, et al (2016). Functional and genetic heterogeneity of distinctive leukemic stem cell populations in CD34- human acute myeloid leukaemia. JEM 213:1513-1535 (2016).
  2. Broudy, V.C., Stem cell factor and hematopoiesis. Blood, 1997. 90(4): p. 1345-64.
  3. Buono M, Facchini R, et al. A dynamic niche provides Kit ligand in a stage-specific manner to the earliest thymocyte progenitors. Nat Cell Biol. 2016 18:157-67.

For further information please contact Professor Paresh Vyas