John Goldman Fellows 2016

Dr Edwin Chen

Dr Edwin Chen, University of Leeds

Project title: Role of Fanconi Anemia Core Complex in Dysplastic Megakaryopoiesis and Myelofibrosis

Summary:
Myelofibrosis is a fatal bone marrow cancer. The disease is caused by excessive secretion of factors by cancerous platelet-producing cells called megakaryocytes.  These secretions cause the replacement of normal bone marrow tissue with fibrous scar tissue.

Dr Chen’s team can successfully recreate this pathological bone marrow environment in the laboratory, and their preliminary research data show that reduced levels of a protein complex called FANCcore leads to more myelofibrosis.

Dr Chen’s team hypothesise that loss of the protein complex FANCcore increases the growth of myelfibrosis by altering megakaryocytes. Dr Chen uses both human tissue cultures and mouse models to examine the cellular and molecular changes to megakaryocytes following the absence of the FANCcore complex and to understand how these changes cause myelofibrosis.

The team hopes that by focusing on the role of FANCcore in megakaryocyte biology, they can reveal new ways to treat myelofibrosis.


Dr Javier Munoz

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

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

Summary:
Leukaemia is blood cancer where malignant immune cells colonise the immune system 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.

Dr Muñoz and his team 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 the ability of cells to move needs to be explored.

This project will define how these protein receptors send signals into the nucleus and how this affects DNA structure to cause the cancer to spread.

The findings from Dr Muñoz’s research will help the team understand how cancer cells move through the body and will enable the design of new personalized treatments for blood cancers.



Dr Zerilli

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

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

Summary:
Every person’s cancer is different and every cancer cell is different within the cancer.

For scientists and doctors to more accurately predict the outcome of treatment, we need to be able to better understand the types and number of DNA mutations present in individual cancer cells.

Dr Rose-Zerilli’s research aims to 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’ cancer cells present in individuals that remain either stable or whose cancer develops, eventually requiring treatment.

The aim of this research is to understand how cancer cells evolve into specific leukaemias that do or do not require treatment and the type of evolution, or combination of mutations that makes some leukaemias difficult to treat more effectively.


Dr Sergey Krysov

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

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

Summary:

The growing understanding of the protein markers on the surface of cancer cells helps to improve the success rate of blood cancer treatments.

According to the Office for National Statistics, Chronic Lymphocytic Leukaemia (CLL) is the most common malignant blood disease. Sadly, despite recent advances in drug development, CLL remains incurable and can transform into a highly aggressive form of cancer.

There are newly-approved drugs designed to block the function of the cancer cells. They do this by targeting the signalling functions of these proteins that reside on the surface of the cancer cell. And while they have entered the clinic, and are revolutionising treatment, they are sadly prohibitively expensive in most cases.

Dr Krysov’s research aims to unravel the control of the surface proteins and signalling inside CLL cells. If we better understand how these proteins and signalling functions work, we may be able to provide new targets for future drugs. Not only this, but we may be able to create treatments to work in tandem with the drugs already available, and optimise their use.

This research aims to investigate the effects of the factors that can directly influence the presence of the surface proteins and the subsequent effects in malignant cells.



Dr Xu Huang

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

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

Summary:
The survival rate of Acute Myeloid Leukaemia (AML) is poor, and more research is urgently needed to improve the prognosis for AML patients.

It is now accepted that there are rare cells within the cancer called leukaemia stem cells (LSCs) that are responsible for the progression of AML within the body.

Dr Huang’s team have already identified a group of proteins including EPC1 and EPC2, which are required for LSCs to function, but are much less important to normal, healthy blood cells. The team’s research now aims to further understand these critical proteins and identify how LSCs interact with other proteins to keep the leukaemia cells functioning. They hope to better understand just how essential these molecules are to the growth of AML.

Their research will provide a better understanding of LSCs behaviour and form the basis for developing innovative new drugs for use in future AML cancer treatment.