John Goldman Fellows 2017

Dr Lisa Hopcroft

Dr Lisa Hopcroft, Institute of Cancer Sciences, University of Glasgow

Project Title: Exposing the interdependent mechanisms of the leukaemic stem cell and the leukaemic niche in chronic myeloid leukaemia using integrative network and systems biology

Summary:

Chronic myeloid leukaemia (CML) is a blood cancer that arises from mutated stem cells in the bone marrow. There is evidence to suggest that, over time, the bone marrow becomes “pro-leukaemic”; that is, it changes to promote the survival of potentially cancerous mutated stem cells over non-mutated ‘normal’ stem cells. To eradicate these mutated stem cells and cure CML, we need to understand not only the cells themselves but also how the bone marrow protects them.

Dr Hopcroft’s team are comparing patterns of gene activity from three different groups of cells: mutated and non-mutated stem cells from Chronic Myeloid Leukaemia patients and normal stem cells from healthy donors.

The team hope to achieve two aims with their research. Firstly, they hope to reveal how gene activity is controlled within the mutated stem cell.

Dr Hopcroft and her team already know that three particular genes are important, but they want to work out exactly how they cooperate. To do this they are using computer-based methods using existing knowledge about which genes interact with each other to analyse the patterns of gene activity and work out to what extent these three genes show cooperative activity.

Secondly, by comparing non-mutated stem cells from CML patients and normal (non-mutated) stem cells from healthy donors, they are aiming to discover what effect the pro-leukaemic bone marrow environment has on stem cells in CML patients.

Understanding both of these aspects of CML will help to expose weaknesses of the disease that could be exploited by new therapies.


Dr Cristina Pina

Dr Cristina Pina, University of Cambridge

Project Title: Linking metabolism and epigenetics in acute myeloid leukaemia 

Summary:

Acute myeloid leukaemia (AML) has a 5-year survival of just 30% and new treatments are urgently required. Leukaemia cells process (metabolise) the nutrients they require differently to normal cells and there is substantial interest in finding treatments that will target the way leukaemia cells break down and utilize their nutrients. 

Some products (metabolites) resulting from the nutrient breakdown are known to be involved in modifying proteins that bind DNA which has the ultimate effect of controlling whether genes are switched on or off. Dr Pina has recently studied AML cells and identified two genes of interest, MAT2A and KAT2A. These two genes may be involved in the use of metabolites and subsequently how leukaemia –related genes are switched on and off. Dr Pina plans to remove the MAT2A gene from patient AML cells and study the effect. The project aims to identify weaknesses in leukaemia cell metabolism that could lead to potential treatments for AML.



Dr Maria Teresa Esposito

Dr Maria Teresa Esposito, University of Roehampton

Project Title: Understanding the role of phosphatase PP2A on chemotherapy resistance of Mixed Lineage Leukaemia (MLL)

Summary:

Mixed Lineage Leukaemia (MLL) is a very aggressive blood cancer and commonly diagnosed in children. Typically MLL involves changes in DNA and represents an aggressive and drug-resistant form of leukaemia. How MLL leukemic stem cells (LSC) develop resistance to therapy is unknown, although common mechanisms implicated are the manipulation of DNA damage and the ability to evade the cell’s normal growth controls.

Dr Esposito will study a protein called PP2A, an important mediator of response to DNA damage and cell growth control, and found to be inactivated in MLL. PP2A activity can be restored by a number of drug already available for clinical use. The overall objective of this study is to understand the role of PP2A on mechanisms of drug resistance of MLL leukaemia and to design novel targeted treatment approaches to MLL-leukaemia.



Dr Anjali KusumbeDr Anjali Kusumbe, University of Oxford

Project Title: Regulatory Potential of Vascular Niches in Acute Myeloid Leukaemia (AML)

Summary:

Dr Kusumbe is looking into the specific blood vessel and cellular environment (called ‘vascular niches’) within the body where AML can develop.

However, treatments aimed at inhibiting vascular growth have not improved patient outcomes, which suggests the relationship between the cancer and the blood vessels is not as simple previously thought.

Dr Kusumbe’s work has already shown that blood vessels in bone are diverse and varied and specific blood vessels play different roles in regulating bone and blood cell formation.

This research study hopes to define the way distinct vascular niches regulate AML and unravel the regulatory role of endothelial cells in AML. 3D and 4D imaging will help Dr Kusumbe in her work, which will greatly increase our understanding of the relationship between vasculature and AML, and help in the development of better treatments for the Acute Myeloid Leukaemia.

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