Vyas Group - Single Cell Biology, Molecular Mechanisms And Genetics of Transformation of Clonal Haemopoiesis to Myeloid Blood Cancer (MDS and AML)

 ABOUT THE RESEARCH

The Vyas laboratory study fundamental processes by which blood stem/progenitor cells that sustain blood cell production throughout life, are gradually perturbed by genetic and epigenetic change resulting in pre-leukaemic and leukaemic transformation to result in the blood cancers, Myelodyplasia (MDS) and Acute Myeloid Leukaemia (AML). 

Genetic and computational modelling of transformation of CH to MDS/AML – from the clinic to the lab and back. 

We have spent the last decade characterising in great detail, the genetic basis, the haemopoietic defects of human clonal haemopoiesis (CH) (Jakobsen et al Cell Stem Cell invited revision) and the changes that lead to transformation to acute and the formation of leukaemia-propagating stem cells (LSCs) and how these LSCs respond to therapy, at the single cell and cell population level (Goardon et al Cancer Cell 2011, Quek et al JEM 2016, Quek et al Nature Medicine 2018; Karamitros et al Nature Immunology 2018; Labuhn et al Cancer Cell 2019; Genua et al Cancer Cell 2020; Turkajl et al Cell Stem Cell 2023). These studies provide a foundational landscape to now accurately model these processes, to study the molecular mechanisms that lead to clonal dominance, gradual differentiation arrest and aberrant self-renewal of LSCs. With colleagues in The MRC Molecular Haematology Unit we have now created strains of genetically modified mice (lineage tracing, conditional and knock-in mutagenesis, fluorescent reporters, genetic disease models) to enable the applicant to introduce leukaemia-causing mutations sequentially to specific haemopoietic compartments in a subclonal manner, and in combinations, exactly as occurs in human disease. The aim is to use muti-omic single cell genomic technologies dissect the contributions to each genetic mutation, and consequent epigenetic change, to understand how aberrant stem/progenitor and differentiated cells contribute to the disease phenotype. Critically, these models provide tools to conduct genetic screens and test pharmacological strategies to either reverse the haemopoietic defect, or eradicate tumour propagating LSCs, involved in the aetiology of AMl and MDS. 

Additional supervision may be provided by Professor Claus Nerlov and Professor Thomas Höfer.

Please see the Radcliffe Department of Medicine (RDM) website for information about applications for a DPhil in Medical Sciences with groups based in RDM.

TRAINING OPPORTUNITIES

Training will be provided in HSC and progenitor biology, inflammation and how it provides a selective advantage, biology and treatment of myeloid malignancies, transcription factor biology and cytokine biology. From a methods point of view the applicant will conduct and be given experience and training in the wet lab molecular techniques and advanced computational analysis required for multi-omic single cell analysis of HSC/progenitors, advanced flow cytometry including FASC sorting, in vitro and in vivo CRISPR/Cas9-based genome editing screens and library screening technologies, advanced mouse genetics, bioinformatics. Candidates will also have exposure to mathematical modelling and machine learning.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

PUBLICATIONS