Throughout our life cells divide, and as they do so opportunities for mutations in our DNA arise. As a result, all humans are a mosaic of different genetic clones, with a variation of DNA mutations in every cell of our body.
Over time some of these mutations result in increased or uncontrolled cell division, resulting in certain cells becoming overrepresented and the heterogeneity of the overall pool of cells for that cell type is reduced.
As we grow older this is what happens in haematopoietic stem cells (HSCs), a type of long-lived cell that produce all the blood cells in the body. When HSCs acquire mutations that give them a clonal advantage, the blood cells they produce are over-represented and this is known as clonal haematopoiesis (CH). When the cells harbouring the mutation make up more than 4% of circulating blood cells, this is referred to as clonal haemopoiesis of indeterminant potential (CHIP). The incidence of CH rises with age, with 20% of people over the age of 70 have CH.
Research to date shows that CH is correlated with two medical problems. First, there is a two-fold increased risk of death from cardiovascular disease. It is thought that the mature blood cells generated by clonally-advantaged HSC are ‘pro-inflammatory’ and that this may lead to heart disease, particularly with damage to blood vessels supplying blood to the heart.
Secondly, there is a 12-fold increased risk of death from blood cancers. We now know that for older patients who develop blood cancer, especially myeloid blood cancer, CH can be the first step on the road to the disease, and this is through to begin 3-15 years before cancer manifests.
The healthy haematopoietic system is maintained by a population of self-renewing haematopoietic stem cells (HSC). These give rise to progenitor cells that differentiate into red cells, white cells and platelets. Mutations occurring in HSC may give rise to clonal haematopoiesis and often affect genes involved in epigenetic regulation. This clone may expand but maintains the ability to produce mature blood cells. Acquisition of further mutations in this clone may lead to uncontrolled proliferation of immature cells and leukaemia.
Prof Paresh Vyas and his team are investigating the mechanisms by which CH HSC gain a clonal advantage. In the MARCH study, led by an MRC Clinical Training Fellow, Dr Asger Jakobsen, Radcliffe Department of Medicne, and in close collaboration with surgeons in the Nuffield Department of Orthopaedic Surgery, Rheumatology and Musculoskeletal Sciences, they have been collecting bone marrow samples from otherwise well patients having hip-replacement operations.
The approach they are taking is to purify both normal, and clonally abnormal, HSC and their progeny from individual subjects. They are studying these cells at a single-cell level using state of the art single cell genomics, to study how they respond to their environment using in vitro and in vivo functional studies. Through this research they aim to understand the basic processes that govern HSC growth, how to predict which individuals will or will not progress on to develop an aggressive blood cancers associated with CH.
By understanding why and which clones go on to contribute to increased cancer risk, targeted therapies can be produced that target these populations over a decade, before the onset of cancer. Similar age-related phenomenon is also seen in the production of many organs that develop cancer including oesophagus, liver and skin, meaning that the implications of understanding this process may have applications for patients with a variety of cancers.
More recently the team, as part of an Oxford-wide COVID research initiative led by Profs Paul Klenerman and Fiona Powrie, Paresh and his team have also been studying patients with COVID-19, to understand if CH has an impact on the clinical course of COVID-19. Part of the severity of COVID-19 disease is due to an exaggerated inflammatory response to the SARS-CoV-2 virus. This work is being conducted in close collaboration with a national initiative on respiratory disease in COVID led by Prof Ling Pei-Ho and CH researchers in Cambridge (Prof Vassiliou) and Stanford (Dr Sidd Jaiswal).
About the team
This work is led by Prof Paresh Vyas, Radcliffe Department of Medicine. His primary focus is to understand the biology of normal blood stem/progenitor cells and how changes in these cells and their environment lead to myeloid blood cancers, especially childhood and adult Acute Myeloid Leukaemia. His laboratory study the functional, genetic, epigenetic properties of heterogeneous populations of leukaemia propagating cells and cells of the microenvironment at a single cell level to understand leukaemia initiation and propagation. He also studies how AML responds to therapies.
The Vyas laboratory collaborates with multiple groups in the MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine Oxford (Nerlov, Roberts, Porcher, Milne Mead and Psaila), Professor Borrow and McMichael (T cell immunity), Majeti laboratory (Stanford) on anti-CD47 therapies, Constantinescu laboratory (Ludwig Brussels) on cytokine receptor signalling and Vassiliou (Cambridge), Jaiswal (Stanford) and Hofer (Heidelberg) laboratories on clonal haemopoiesis. He has extensive collaborations with clinical trials groups in the UK, Europe and United States.
The application of his CH work to the COVID-19 pandemic is funded by the Wellcome Trust, the National Institutes of Health Research through the Oxford Comprehensive Biomedical Research Centre and the medical Sciences Division of University of Oxford.