Dr Asger Jakobsen, University of Oxford
Project Title: Molecular and Cellular Basis of Clonal Dominance in Myeloid Malignancy
Dr Jakobsen and his team are investigating genetic mutations that turn normal blood cells into abnormal ‘pre-leukaemic’ cells that can go on to cause Acute Myeloid Leukaemia:
Humans produce around 100 billion new blood cells daily to survive. Occasionally mistakes occur in this complex process, which may lead to blood cancer, including Acute Myeloid Leukaemia (AML). AML is the most common aggressive blood cancer in adults with 3000 new cases per year in the UK, and unfortunately the majority still die of their disease within 6 months of diagnosis. A better understanding of the biology of Acute Myeloid Leukaemia is needed to improve the outcome for these patients.
AML arises as a result of multiple mistakes, or mutations, in genes that control blood production. These mutations usually occur in a step-wise manner over time in a small pool of blood stem/progenitor cells (the cells that give rise to all the blood cells we need). Recently it was discovered that some of these mutations are commonly found in the blood cells of healthy older people who do not have yet have blood cancer. These mutations appear to make the cells grow more than is normal, so that over time they dominatae the bone marrow (where blood is produced), and increase the risk of developing blood cancers in the future.
The most common of these mutations occur in genes which control "epigenetic" marks on the DNA. Epigenetic marks do not affect the DNA sequence, but can contribute to disease as they control how genes are switched on and off.
In this project, Dr Jakobsen and his team will be studying how mutations in these epigenetic regulators turn normal blood stem cells into abnormal "preleukaemic" cells that can go on to cause AML. They are aiming to discover which blood cells get the mutations and which pathways in these cells make them grow abnormally. To do this, they will be studying blood cells from healthy human volunteers who have donated bone marrow samples.
Dr Sandeep Potluri, University of Birmingham
Project Title: Characterisation of Chromatin Landscapes of Pre-leukaemic and Leukaemic Stem Cells in Core Binding Factor AML and their Response to Epigenetic Therapy
Dr Potluri and his team are investigating a potential link between the RUNX1 gene that regulates blood cell development and leukaemia relapse in Acute Myeloid Leukaemia patients who had achieved temporary remission thanks to chemotherapy.
Acute Myeloid Leukaemia (AML) is a relatively common blood cancer that forms a significant proportion of Dr Potluri’s clinical work as a haematologist.
Whilst intensive chemotherapy can achieve temporary clinical remission in about 80% of patients, 5 year survival is only 15% without undergoing procedures such as a stem cell transplant. Consequently, a key clinical question is to understand on a genomic level what is causing these patients to relapse, with a view to preventing relapse in future patients.
RUNX1 is a gene that is of utmost importance in blood cell development and has been dubbed in its research community as the "master regulator of blood cell development". Dr Potluri’s lab has worked on understanding this gene and its interactions for many years and they have considerable expertise. Mutations in RUNX1 also happen to be one of the commonest defects in AML. Dr Potluri and his team aim to investigate this gene with reference to the clinical problems of relapse in Acute Myeloid Leukaemia.