Dr Konstantinos Tzelepis
Stem cells, Cancer, Ageing, RNA modifications
Email: kt404@cam.ac.uk
Laboratory: Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre
Biography
Before joining CSCI, Dr Konstantinos Tzelepis was a group leader at the The Milner Therapeutics Institute, University of Cambridge (UK). Prior to this, he was a Wellcome Trust Sir Henry Wellcome Fellow at Harvard University (USA) and the University of Cambridge (UK). Konstantinos graduated from the University of West Attica (Greece) with a B.S. in Biomedical Sciences in 2009 and then from the Medical School of the National and Kapodistrian University of Athens (Greece) with a M.S. in Cancer Biology in 2010. Konstantinos obtained his Ph.D. in Molecular Genetics from the Wellcome Sanger Institute and the University of Cambridge, in 2017, working on developing one of the first genome-wide CRISPR screening platforms for the identification of cancer vulnerabilities and novel therapeutic targets.
Research Summary
Epitranscriptomics, the modulation of RNA function via its chemical modification, has emerged as a pervasive new mechanism of gene regulation. The role of the epitranscriptome on stem cell fate, maintenance and ageing remains largely unexplored. Similarly, the impact of aberrant RNA modification and editing on oncogenic transformation and cancer stem cell maintenance remains poorly investigated, however early studies suggest that the modification of RNA could be exploited for the development of new therapies for devastating diseases including anti-leukaemia therapies.
The Tzelepis group investigates the relevance of RNA modifications in normal and malignant stem cell biology, with a focus on haematopoiesis. Using sophisticated CRISPR screening platforms, the lab has identified a significant number of epitranscriptomic vulnerabilities of acute myeloid leukaemia (AML) and have gone on to investigate some of these in detail, including the m6A writer METTL3 (Barbieri et al, Nature, 2017) and the m7G writer METTL1 (Orellana et al, Mol Cell, 2021). Notably, their latest study of the first-in-class METTL3 inhibitor (Yankova et al, Nature, 2021) provides strong proof-of-concept that RNA-modifying enzymes represent a new avenue for anti-cancer therapeutics.
Future aims include study of selected RNA modifying enzymes which I identified as essential for either normal or leukaemic haematopoietic stem cells and whose function is currently unknown or incompletely understood with a particular focus on how particular RNA modifications regulate cell fate, differentiation, ageing and leukaemogenesis in normal and malignant haematopoiesis.
Key Publications
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Yankova, Blackaby et al. Small molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature 2021
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Orellana et al. METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation. Molecular Cell 2021
- Mikutis et al. meCLICK-Seq – a substrate-hijacking and RNA degradation strategy for the study of RNA methylation. ACS Central Science 2020