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Dr Chris Booth completed his DPhil under the supervision of Adam Mead and Sten Eirik Jacobsen (NDCLS, MRC WIMM). Chris led a study that provided experimental evidence that the phenotypic and gene expression profiles of a cancer can be traced back to those of the cell of origin

I joined RDM in 2012 as a research assistant in Professor Adam Mead group, having recently completed my ChrisBoothPhoto2.jpgundergraduate studies in Biochemistry at the University of Cambridge. With Professor Mead, I began work on a project using mouse models to understand the origins of malignant stem cells in haematological disorders. We focused on the roles of the transcriptional regulators Ezh2 and Runx1, which are frequently co-mutated in patients.

Receiving a WIMM Prize Studentship in 2013 meant that I was fortunate to be able to continue this work as a DPhil student, under the supervision of Professors Mead and Sten Eirik Jacobsen. During my DPhil, I used targeted inactivation of Ezh2 and Runx1 to generate a mouse model of early thymic progenitor (ETP) leukaemia, a treatment-resistant subtype of T-cell acute lymphoblastic leukaemia. The leukaemia in this mouse model can be propagated by ETPs, confirming for the first time that these cells carry the potential to become leukaemic stem cells (LSCs).

I was able to show that upregulated oncogenic gene expression is in part driven by the loss of Ezh2 in this model, which leaves the leukaemia vulnerable to therapeutic targeting with BET inhibitors. Interestingly, targeting the same two mutations to haematopoietic stem cells (HSCs) rather than early lymphoid progenitor cells results in a distinct myelodysplastic syndrome phenotype. These findings illustrate the importance of the cell of origin in determining the subsequent phenotypic profile of a malignancy.

After completing my DPhil thesis in 2017 I stayed on for another year with Profs Mead and Jacobsen as a postdoctoral researcher. During this time my work on ETP leukaemia was published in the high-impact journal Cancer Cell. Subsequently, another project I had contributed to alongside Dr Wen Hao Neo, examining the role of Ezh2 in the emergence of HSCs during development, was published in Blood. I was also pleased to have been able to contribute to studies by the Mead and Jacobsen groups published in Nature Medicine and The Journal of Experimental Medicine.

The mentorship I have received from Professors Mead and Jacobsen as a member of RDM has been truly exceptional, and has left me inspired to pursue a career in haematological research. To that end, in 2018 I moved to Boston, USA to become a Research Fellow in Dr Andrew Lane's research group at the Dana-Farber Cancer Institute.