Elucidating the Immune Landscape in Clonal Haematopoiesis of Indeterminate Potential and Progression to Haematological Malignancy

点击翻译按钮获取中文摘要

Clonal Haematopoesis of Indeterminant Potential (CHIP) is a term used to describe the presence of blood cancer-causing genetic alterations in otherwise normal blood cells. CHIP is a common finding in normal people as part of the ageing process. It is seen in 1 in 10 people over 70 years. The presence of CHIP increases the risk of blood cancers, such as myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) , as well as heart disease. However, this increase in risk is relatively modest. Therefore, it is important to understand which individuals with CHIP have the greatest risk of these more severe conditions and why.The goal of being able to identify CHIP and those at greatest risk of evolving into cancer is to find ways to avoid or delay this happening. This is vitally important in MDS and AML, especially in older people, as due to the toxic nature of the treatment these conditions are incurable. It is relatively straight forward to test patients for CHIP, however, we do not know much about which patients will progress to blood cancer. This vital knowledge is a big gap in our understanding of CHIP because we cannot provide appropriate further information to affected patients. An area of increasing interest in cancer is understanding how our own bodies immune system reacts to cancer cells (termed cancer immunology). Cancer cells commonly develop methods of hiding themselves from the immune system to help them grow. New treatments have been developed in the past few years that can help the immune system to see and destroy cancer cells, or create artificially modified immune cells that target the cancer cells specifically. Effective immune responses against cancer cells (particularly in 'T-cells'), are the most important defence that the body has against the development of cancer. Interestingly, T-cell responses directed against CHIP/AML-associated mutations have been found. However, the role of the immune system in helping to control CHIP, and its progression to MDS/AML are not clear. We think that active immunity towards CHIP cells may protect patients from developing MDS/AML. The goal of this project therefore is to understand in detail the immune cells and how they work in patients with CHIP. We will investigate if CHIP-specific T-cell responses can be identified and if these predict progression from CHIP to MDS/AML. This project benefits from access to a unique resource: the English Longitudinal Study of Ageing (ELSA). ELSA is a long-running study into ageing (since 2002). As part of the study, participants are interviewed about their health and blood samples taken every other year. It is therefore perfectly placed to investigate CHIP and its progression/complications over time. We will screen these samples for mutations to identify individuals with CHIP and assess how the CHIP progresses over time. In conjunction with ELSA, will with then collect new blood samples from specific individuals with CHIP for more detailed analysis of the immune cells.Using these samples and the world-class expertise in cancer immunology in the host institution, we will look at the range of different cells in the immune system in CHIP. Particularly we will assess the types and function of T-cells and how these change with CHIP progression. We will also look at other types of immune cells in the blood, that may be altered by CHIP. We propose a particularly exciting and novel experiment using mutation-specific markers to separate out the blood cells carrying the CHIP mutations to compare them to normal cells. Given the poor prognosis of MDS/AML in older people, the long-term aim of this research is to improve understanding of the biology of CHIP and its progression to MDS/AML, to progress the field towards strategies aimed at modifying the risk of developing of blood cancer and other CHIP-associated health problem.