Age-Related Changes in the Blood
As we age, there are many factors that can cause our blood stem cells to decline in quality leading to disease and potential cancers. Research into age-related changes in the blood is so important as there are still a lot of unanswered questions that surround the topic. Dr Kirschner’s research group at the University of Glasgow and the Cancer Research UK (CRUK) Beatson Institute have been studying how ageing contributes to blood cancer development. The main aim of Dr Kirschner’s research is to find better treatments for blood cancer.
The Effects of Cellular Ageing and Senescence on Cancer Development
Simply put, senescence is the cell’s process of becoming old. When a cell becomes senescent it no longer continues to contribute to the functioning of the body and no longer makes new cells. A normal cell in this situation would die off, whereas senescent cells do not.
Senescence can have both positive and negative effects on cells. For example, a positive effect of senescence is that a cancerous cell can become senescent meaning that it can no longer multiply further. Therefore, senescence can act as a mechanism of tumour suppression. However, senescent cells accumulate with age and release chemicals that can cause inflammation and thereby create a pro-cancerogenic environment, potentially promoting the onset of cancer. There are various stressors that can cause cells to become senescent, such as damage to the cell’s genetic information- namely DNA. The Kirschner lab is trying to understand the fundamental mechanisms of senescence to further help dissect the positive and negative effects of senescence on the body.
Clonal Haematopoiesis Occurs in Healthy Aged Individuals
Clonal haematopoiesis (CH) is the name given to a phenomenon where a mutated blood stem cell gains dominance and self-renews and produces multiple mutated blood cells at an excessive rate, therefore, creating a population of mutated blood cells. Blood stem cells are found inside our bones, in the bone marrow. Clonal means ‘a group of cells produced by a single cell’ and haematopoiesis is ‘the process that where blood cells are created.’ These mutated cells then have different DNA from the rest of the body's healthy cells. CH has many different consequences on the body due to the mutations that it causes in the cells, these include an increased risk of cardiovascular disease and blood cancers such as leukaemia. CH becomes more prevalent with age, with many people diagnosed with CH being over the age of 60. This is because as you age, your stem cells have a higher risk of mutating, therefore putting older individuals at risk. It is important to study CH as it provides insight into the process of ageing and how ageing can impact our body when mutations occur.
Myeloproliferative Neoplasms are an Early-Stage Blood Cancer
Myeloproliferative neoplasms (MPNs) are a group of blood cancers originating from blood stem cells. The blood stem cells of an individual with an MPN contain a mutated gene that causes stem cells in the bone marrow to incorrectly produce blood cells. Every time a new blood cell is created the mutated DNA is passed on. A normal blood stem cell would create a variety of blood cells such as red blood cells, platelets, and white blood cells. However, in the case of MPNs, blood stem cells make the wrong amount of mature blood cells. This can either result in too many or too few of a certain blood cell type being made, which alters the viscosity of the blood. For some people, an MPN is an acquired disease, that can be developed at some point in their life. However, other people can be born with the mutation and the disease will manifest itself later in life.
There are three main types of MPNs: Essential Thrombocythemia, Polycythaemia Vera and Myelofibrosis. Even though many people can live a normal life with an MPN, it is still an extremely important disease to study for many reasons. MPNs have the potential to change into more severe forms of cancer such as Leukaemia, which is a more serious form of blood cancer.
Therefore, having a developed understanding of MPNs could help figure out how to prevent the progression into severe forms of blood cancer. Another reason it is important to study MPNs is that there are many side effects that MPNs can produce such as being prone to bruising, having poor circulation, along with the more severe potential side effects such as clotting and heart attacks.
Created in BioRender, inspiration taken from https://www.cancer.gov/types/myeloproliferative/patient/chronic-treatment-pdq. This image is showing the pathway of how a blood stem cell would create blood cells including red blood cells, platelets, and white blood cells.
Essential Thrombocythemia (ET) is a type of MPN where a mutated blood stem cell creates platelets, in excess, causing the blood to have an abnormally high platelet count. Having a high platelet count is an issue as platelets are cells that stick together in the blood to form clots, and when there are high numbers of these platelets there is the potential for the clots to block a blood vessel. Consequently, people with ET MPN have a considerable risk of stroke and heart attack. Blood thinners such as aspirin or warfarin can be taken by ET patients to help reduce the risk of clotting. Many people with ET can live a normal life and their life expectancy is not affected.
Polycythaemia Vera (PV) is a type of MPN that is caused by a blood stem cell overproducing red blood cells. This leaves PV patients with an abnormally high red blood cell count that causes the blood to be thicker than it should be, putting them at risk of clotting. The spleen is an organ in our body that has many functions, one of which is to store a percentage of our red blood cells. In individuals with PV, their spleen can become enlarged due to the excess of red blood cells that are being produced is stored in the spleen. This therefore can reduce the number of healthy red blood cells in the body making individuals with PV more prone to getting infections. Another risk associated with PV is clotting which may cause heart attacks and strokes. PV patients are at increased risk of these thrombotic events due to the increased viscosity of their blood due to high red blood cell numbers.
Myelofibrosis (MF) is the third main MPN where the accumulation of mutated blood cells causes the bone marrow to become inflamed, which as a result, creates a build-up of scar tissue inside the bones. This causes many complications for MF patients, as the build-up of scar tissue prevents the normal production of blood cells. As a result, inadequate levels of red blood cells are produced which causes acute anaemia. Other symptoms of myelofibrosis include extreme fatigue due to anaemia, bruising, and infections due to low white blood cell count. There is currently no treatment, only methods to manage the symptoms. These can include blood transfusions to help with anaemia, aspirin use if there is a high platelet count, along with the use of certain hormones to help stimulate the body to produce blood cells.
The Relationship Between Clonal haematopoiesis, MPNs and Leukaemia
Individuals with CH and individuals with an MPN have an increased risk of developing myelodysplastic syndromes or acute myeloid leukaemia. The progression of CH or MPN towards cancer happens when the mutated cells gain an advantage and outgrow their neighbouring cells, therefore, breaking the regular balance within a tissue. They can gain this advantage by increasing the rate at which they make more stem cells. As CH or MPN is driven by mutations in the DNA of blood cells, the state of the cell can determine whether the disease progresses to leukaemia, as having many damaged blood cells increase leukaemia risk. This is because the high amounts of damaged blood cells can more easily gain more gene mutations over time, thereby further dividing and overcrowding the blood system. This reduces the number of healthy blood cells that can be created and function as normal and leads to blood cancer.
Below is an image showing the progression of a blood stem cell when a mutation occurs that causes CH.
Created in BioRender, inspiration taken from https://www.nature.com/articles/s41375-021-01337-8. Pathway of the development of clonal haematopoiesis into cancerous cells, inflammatory cells, and stem cells with decreased ability to create regular blood cells.
What Research is Ongoing at the University of Glasgow with CRUK?
At present, there is no ‘cure’ for most blood cancers, there are only methods to manage the disease. Therefore, Dr Kirschner’s research team aims is to find a treatment for the disease.
A key aim in the lab is to find out why exactly that blood cancer prevalence rises with age to try to find more ways to treat various blood cancers in less invasive ways. One method that has been used to study an abnormal cell is the use of specialised technology that allows just a single cell to be examined rather than a cluster of cells. Single-cell studies allow researchers to focus on an individual cell's DNA. These single-cell studies are important as it is known that only a small group of cells maintain a disease, therefore, if a small group of cells can be studied, more insight can be given into the disease. By using single-cell approaches the lab found that senescent cells signal to other cells via cell-to-cell contact meaning they are passing signals to cells that they are neighbouring. In addition, the lab identified different types of senescence cells. Further studies into the consequences of having different types of senescent cells in your body are currently undergoing.
We know that age-related changes in the blood such as CH cause abnormalities in the blood cells, along with MPNs. For the population’s blood samples to be tested to detect abnormalities early to then assess the risk of developing blood cancers and leukaemia would be an expensive process. The Kirschner lab together with colleagues at the University of Edinburgh studied CH in a population-based manner. They studied ageing blood cell mutations using pre-existing data from the Lothian Birth Cohort (LBC) to help detect mutations in blood cells. The LBC is a bank of data containing samples and records of health from 1,500 people, with samples and health records being taken of these individuals up to five times every three years, from the ages of 70 and 79. This cohort allowed Dr Kirschner, and colleagues have followed blood stem cells in individuals over 15 years which allowed the group to establish how cells with different types of damage to their DNA multiply in the blood over time. Knowing which type of damage lets cells grow fastest will help us predict the risk of developing blood cancer before it occurs.
Erin Currie (UofG Undergraduate Student - Final Yeat Public Enagagment Outreach Project)