Dr Edwin Chen, University of Leeds
Dr Javier Redondo Muñoz, University of Manchester and IiSGM, Madrid
Dr Matthew Rose-Zerilli, University of Southampton
Dr Sergey Krysov, Queen Mary, University of London
Dr Xu Huang, Paul O’Gorman Leukaemia Research Centre, Glasgow

Edwin ChenDr Edwin Chen, University of Leeds

Role of Fanconi Anemia Core Complex in Dysplastic Megakaryopoiesis and Myelofibrosis

Project Summary:
Myelofibrosis is a fatal bone marrow cancer. The disease is caused by excessive secretion of factors by cancerous platelet-producing cells called megakaryocytes that causes the replacement of normal bone marrow tissue with fibrous scar tissue. We can successfully simulate this pathological bone marrow environment in the lab, and our preliminary data show that reduced levels of the core Fanconi protein complex (called FANCcore) worsened the fibrotic phenotype. We therefore hypothesise that loss of FANCcore promotes myelofibrosis by altering the physiology of megakaryocytes. In our research, we leverage human tissue cultures and mouse models to examine the cellular and molecular changes to megakaryocytes following FANCcore deletion and to understand how these changes instigate myelofibrosis. We hope that by drilling down on the role of FANCcore in megakaryocyte biology, we can reveal new ways to treat myelofibrosis by targeting FANCcore-specific vulnerabilities.

Javier MunozDr Javier Redondo Muñoz, University of Manchester & Instituto de Investigacion Sanitaria Gregorio Maranon, Madrid

How integrins drive chromatin changes that modulate nuclear mechanics and migration of leukaemia cells

Project Summary:
Leukaemia is blood cancer where malignant immune cells colonise the immune organs and stop them from making healthy blood cells. The nucleus, enclosing the cell DNA, is the biggest structure inside cells. It must alter its physical properties (shape, size, stiffness) to allow the lymphocytes to squeeze through narrow spaces in tissues. The processes that allow this to happen are currently unknown. I have obtained evidence that signals coming from a protein receptor (integrin) on the surface of leukaemic cells alter the DNA structure. However, how this leads to changes in the physical properties of the nucleus and affects cell migration needs to be explored.

This project will define how integrins sends signals into the nucleus and how this affects DNA structure to cause the cancer dissemination. The findings from this project will help us understand how cancer cells move through the body and will enable the design of new personalized treatments for blood cancers.

Rose ZerilliDr Matthew JJ Rose-Zerilli, Cancer Services Unit, University of Southampton

Single-cell profiling of Chronic Lymphocytic Leukaemia to understand cancer intra-tumoural heterogeneity and evolution

Project Summary:
Every person’s cancer is different and every cancer cell is different within the cancer. If we (scientists, doctors and patients) are to tackle blood cancer face on and provide better methods to predict clinical outcome we need to understand the number and types of DNA mutations present in individual cancer cells. This research proposal will separate single leukaemia cancer cells and analyse them in micro-fluidic based machines to detect the mutations present in each cancer cell. This data then can be used to generate evolutionary maps of the populations of cancer cell present in individuals that remain stable or develop progressive disease, requiring treatment. The aim is to understand how cancer cells evolve into leukaemia’s that do or do not require treatment and the type of evolution, or combination of mutations that makes some leukaemia’s difficult to treat effectively.

Sergey KrysovDr Sergey Krysov, Barts Cancer Institute, Centre for Haemato-Oncology, Queen Mary, University of London

A novel B-cell receptor – nuclear repressor ZEB2 axis that defines the clinical outcome in chronic lymphocytic leukaemia

Project Summary:
The growing understanding of the protein markers on the surface of cancer cells provides a means for improving the success in the treatment of blood cancer. According to the Office for National Statistics, Chronic lymphocytic leukaemia (CLL) is the most common malignant blood disease. Importantly, despite of recent advances in drug development, CLL remains incurable and can transform into a highly aggressive form. Newly approved drugs designed to interfere with the cancer cell functions via targeting the signalling from the surface proteins, have now entered the clinic and while revolutionising treatment are prohibitively expensive. Unravelling the complex regulation of the surface proteins and signalling inside CLL cells will provide new targets for future therapies and optimise application of drugs already in clinical use. This project is designed to investigate the effects of the factors that can directly influence the surface proteins expression and mediate their downstream effects in malignant cells.

Xu HuangDr Xu Huang, Paul O’Gorman Leukaemia Research Centre, University of Glasgow

“Omics” approach to delineate the critical epigenetic regulatory machinery selective for acute myeloid leukaemia (AML) stem cell function

Project Summary:
Acute myeloid leukaemia (AML) poses a significant clinical problem due to its poor prognosis. It is now accepted that there are rare cells within the leukaemia blast population called leukaemia stem cells (LSCs), which are responsible for cancer progression. New therapeutic solutions which are able to selectively kill LSCs, hold great promise to cure leukaemia. We identified a group of proteins including EPC1 and EPC2, which are selectively required for LSC function, but much less important to the normal healthy blood cells. In this proposed project, we aim to further characterise these critical proteins by using multiple advanced techniques, and disclose how it interacts with other proteins to sustain leukaemia cell function as essential molecular machinery in AML. Our study will provide a better understanding of LSCs behaviour and form the basis for developing innovative drugs for use in future AML treatment and perhaps for other types of cancers.