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By Kristy Tsang, on 13 November 2023
In this interview as part of the Early Career Researchers series, recognising the amazing translational work being done by postdocs and non-tenured researchers at UCL, Dr Yang Li highlights her Small Molecules Therapeutic Innovation Network (TIN) Pilot Data Scheme awarded project, developing a novel approach to develop the drug for MYB-dependent cancers.
My project is titled “Structural characterisation of MYB/TAL1 interaction using crosslink Mass Spectrometry”. As it suggests, I aim to resolve the structural association of a prominent oncogene complex MYB/TAL1/GATA3 that maintains T-cell lymphoblastic leukaemia (T-ALL).
MYB itself is a well-known haematopoietic transcription factor that tips the balance between cell proliferation and differentiation in multiple blood cell lineages. It is often over-expressed in blood cancers, and these genetically heterogeneous diseases often rely on high MYB levels to sustain their cancer status, a process known as oncogene addition. We here use a T-ALL cell line JURKAT as a model to isolate and characterise the binding of MYB to the previously studied cancer-driving TAL1 network, where we believe the loss of MYB by future therapeutics can target acute leukemic cells for cell death while healthy cells that has regular MYB expression can be spared.
In parallel to the proteomics, I also designed and tested in vitro the interaction between the MYB/TAL1 proteins. We used a non-cancer cell line system to validate the protein-protein interaction of MYB/TAL1, and with which minimum components of the TAL1 network can form the core oncogene machinery. This can help us understand the importance of each component, and in this study, we discovered the tri-protein complex MYB/TAL1/GATA3 has the most functional significance to the assembly of this cancer-driving complex.
Transcription factor MYB has an increasing appreciation in the past decade to be a potent anti-cancer target. It is rarely mutated and very often overexpressed in broad range of solid tumours such as colon and pancreatic cancers, and most breast cancers with positive oestrogen receptor phenotype (that it >70% of cases). Crucially, almost all forms of acute leukaemia patients express high levels of MYB and these blasts depend on MYB for survival. Previous animal works and human primary cell experiments further ascertain that MYB suppression is specifically harmful to cancer cells but not healthy cells, suggesting an ideal therapeutic window there MYB degradation is critically targeted to uncontrolled cell proliferation. Despite all the promising anti-cancer effect for MYB, and several publications discovering compounds suppressing MYB at protein level, there remains no MYB targeting drugs beyond laboratory. This is largely because transcription factors are inherently difficult to target as they bind to DNA highly dynamically, and that one often acts within a large, compact protein complex. Therefore, we need structural understanding of MYB before we can design a potent anti-MYB drug. We believe this project will begin the journey to reveal how MYB associates itself within the TAL1 oncogene complex in T-ALL cells, and identify which core subunits, in addition to MYB, are key to hold such complex together. By identifying these interaction hotspots, we can more confidently and specifically design, select and manipulate compounds to produce a robust drug for MYB-dependent cancers.
Our project is very focused on a major oncogene complex in T-ALL which we have been hoping to target with small molecules. Previous work already suggested possible ways to suppress MYB with existing compounds, but the efficacy and targeting specificity remain elusive in human related settings. We therefore wanted to investigate the actual structure of this complex and explore the possibility of small molecules that can fit into a therapeutic strategy. Given this is largely a piloting work and I am an early career researcher leading the study, I find the Small Molecule TIN an excellent support. The funding and research remit was specifically designed to promote the early stage of translational studies and to help young scientists like me who has limited resources to explore new areas. I was able to collect exciting preliminary data for large funding application and build a profile for my own career development. I was also able to collaborate with experts of proteomics and leukaemia, without whom this project would not have gone this far. I was very glad and grateful that UCL has such scheme in place. As a wet lab scientist, I really appreciate opportunities like this for us to test a somewhat challenging but potentially fruitful idea.
The entire application process has been straightforward and well organised. I first discovered this scheme via UCL emails and the forms are very simple to follow. I was able to obtain responses very promptly and had sufficient time to prepare for each different stage. As the scheme was largely designed for translational studies and the interview was given as a form of “idea pitch”. I was able to participate in the ACCELERATE training workshop to learn about skills for pitching ideas. This has been an educational and eye-opening experience as we often never have this form of presentation. It was very useful to learn the skill of delivering a punchy idea so quickly and clearly to audiences from different research field. I was very glad to receive the funding and absolutely enjoying working on this innovative project. I was very well supported throughout the entire process, and the few questions I had were addressed immediately.
This project was a highly ambitious one where we planned to structurally characterise the large MYB/TAL1 oncogene complex and to establish an in vitro protein-protein interaction (PPI) model to validate the findings. It was with the help of our expert collaborators at Memorial Sloan Kettering Cancer Centre that we could investigate complex associations using T-ALL isolated oncogene complex and analysing it through crosslinking Mass Spectrometry. This is one of the most comprehensive strategies to dissect a large complex where its components and mechanism of assembly are both incompletely characterised. I was able to establish a strong collaboration with the major scientists in this field, and learned numerous biochemistry assays along the path. Additionally, I have devoted substantial amount of time to set up my own in vitro experiment model to test protein-protein interaction using a luciferase-reporter complementation system. I’ve done so during my PhD between two proteins I studied, but this time it was with two proteins that are interacting with multiple additional components, and both the MYB/TAL1 oncogenes have much more complex structures. We believe the identification of crucial interaction hotspots would ultimately provide solid evidence to further purify and reconstruct the MYB/TAL1 complex for high-precision Cryo-EM structural characterisation, where we can reveal the most druggable epitopes or association motifs that are accessible to small molecules. The Bcl-2 small molecule inhibitor Venetoclax is one exceptional example for structural specific anti-cancer therapeutics, and I believe this study begins the journey to a potential MYB inhibitor or PROTAC in a wide range of cancers.
I am hoping to use the data generated from this scheme to apply further funding from Leukaemia focused charities and Cancer Research UK to pursue the structural characterisation of MYB/TAL1 oncogene complex, and perform more in vitro and in vivo validation of MYB-inhibited cancer phenotypes. I am fortunate to receive advice and expertise from leading scientists in leukaemia research and protein biochemistry, and their help really supported my confidence in wet lab research, and in establishing my own scientific hypothesis. I would continue the collaboration in future, and to expend my knowledge scope to more proteomic studies. During the scheme, I managed to set up further collaborations with other UCL based labs and the recently established cloning facility. I believe these resources broadens my research capacities and allowed me to work more efficiently. The expansion of knowledge and professional connections would substantially strengthen my profile when I apply for funding and become more independent in research.
Dr Yang Li is a postdoctoral research fellow at UCL Cancer Institute. Following her completion of PhD in Immunology, she developed further interest in epigenetics and hence studied gene expression control via 3D genome topology with Prof. Sue Hadjur at the Cancer Institute. She recently joined Prof. Marc Mansour team where she continued to apply her knowledge of chromatin regulation in acute blood cancers, aiming to dissect the complex oncogene network that initiates/maintains T-cell lymphoblastic leukaemia.
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