Summary
Genetic mutations and cancer
Our bodies are made up of trillions of cells. Almost every cell has a nucleus containing a complete set of our genetic material - our DNA.
Inside the nucleus are structures called chromosomes. Tightly packaged up inside chromosomes is our DNA. Genes are short sections of DNA. About two per cent of our DNA carries the instructions to make all the proteins our body needs to function. Proteins are the molecules that actually do all the work in cells. Genes give the instructions and proteins are the building materials made from those instructions. The remaining DNA works behind the scenes controlling how our genes work.
Our cells have a lifespan – they get old and die off. They replace themselves with new cells. To do this they make a copy of themselves and then divide into two. Each time a cell divides, it copies its DNA and sometimes, small copying mistakes can occur, called mutations.
When DNA is damaged, it can change the instructions. Some mutations allow a cell to make too many copies of itself while others stop it from dying and yet others stop repairs from being made. When these happen, a cell can multiply out of control. Over time, the damaged cells build up, creating a cancer. Cancer cells grow because they ignore the normal controls that tell healthy cells when to divide, repair, or die.
Most mutations are harmless, and some are repaired automatically by our cells. Normally, our immune system gets rid of these mutated or altered cells but as we age our DNA repair mechanisms weaken and our immune system becomes less good at this.
In most cases, we don’t know exactly why these mutations happen in some people but not others.
What is MPL?
MPL is a gene that helps manage normal cell growth. It is especially important in making new blood cells.
Your blood cells are constantly being renewed. New blood cells are made in the bone marrow, the soft fibrous tissue inside many bones. Immature blood cells, celled hematopoietic stem cells, develop into different types of blood cells, including white blood cells, red blood cells and platelets. They stay and mature in the bone marrow until needed and then are released into the blood. For more on the blood see Full blood count, Platelets, Haemoglobin, Haematocrit and Reticulocyte count.
Hormones called growth factors stimulate these stem cells to develop into the various types of blood cells. They do this by binding – attaching - to receptors on the surface of the stem cells. Receptors receive these chemical signals and transmit them to the nucleus at the center of the cell, stimulating the cell to make more copies of itself.
The MPL gene makes a protein called thrombopoietin receptor protein. This protein acts as a receptor for thrombopoietin, a growth factor. It works with a signalling pathway inside blood cells called the JAK/STAT pathway. A signalling pathway is a type of chemical reaction that allows the inside of a cell to react to things happening on the outside of the cell.
When the MPL gene develops a mutation, a faulty protein is made which keeps the receptor permanently turned on sending constant "grow" signals down the pathway to the nucleus. Cells keep dividing and making more copies of themselves. As a result, too many blood cells are made, specifically blood cells called platelets, a condition known as a myeloproliferative neoplasm (MPN).
What are myeloproliferative neoplasms (MPNs)?
A disorder in which too many blood cells are made is known as a myeloproliferative neoplasm (MPN). Having a mutation in the MPL gene can lead to two conditions:
Too many platelets - essential thrombocythaemia (ET)
A mutation in the MPL gene causes too many platelets to be made. Platelets are tiny plate-shaped cells in your blood. They bind together to form clots when blood vessels are injured. Having the right number of platelets is essential for proper blood clotting. Having too many platelets for any reason is called thrombocythaemia. When a mutation in the MPL gene causes too many platelets to be made it is called essential thrombocythaemia (ET). For more on platelets and how they form clots see platelet count.
People with ET usually have no symptoms, but some may develop blood clots because there are too many platelets or bleeding because the platelets they are making do not function properly. Symptoms may include tingling in the hands and feet, headaches, dizziness, nosebleeds and easy bruising.
Scar tissue in the bone marrow - primary myelofibrosis (PMF)
The increased cell activity in cells increases the amount of collagen being made.
Collagen normally provides structural support for the cells. Too much collagen causes scar tissue to form in the bone marrow. This is a condition called primary myelofibrosis (PMF).
Over time, the scar tissue crowds out normal blood-forming cells. Because the marrow is fibrosed (filled with scar tissue), blood cell production shifts to the spleen and liver, causing them to get bigger.
PMF is a serious disorder that can eventually turn into a type of leukaemia called acute myeloid leukemia (AML). Some people with PMF have no symptoms. People who do have symptoms may have those that are associated with severe anaemia (when you have too few red blood cells or your red blood cells are too small), such as fatigue and weakness.
MPL blood cancers are caused by somatic mutations
MPL mutations are termed somatic. This means they occur during life. They are not inherited - you were not born with them, and you cannot pass them on to your children. Only abnormal blood cells carry the cancer-causing DNA mutations.
Your results
The MPL mutation test is typically ordered as a follow-up test if you have had a Full Blood Count which has shown a high platelet count. An erythropoietin test may also be used.
Tests can be used to rule out other possible disorders such as iron studies, to exclude iron deficiency anaemia with reactive thrombocytosis, inflammatory markers such as CRP, ESR. Genetic BCR-ABL1 testing may be ordered to rule out chronic myeloid leukaemia (CML).
Mutation testing for the gene JAK2 is often ordered at the same time since both MPL and JAK2 mutations can lead to the same symptoms.
If the MPL W515L or W515K mutation is detected and you have other supporting clinical signs, then it is likely that you have an MPN. If you are negative for an MPL mutations, you may still have an MPN. You could have mutations in other genes such as JAK2.
Types of MPL mutations
Mutations can develop in different parts of the MPL gene. These are named for the specific location in the MPL gene where the mutation has occurred. The main mutations that are tested for are MPL W515L and MPL W515K.
Mutations in other genes can also cause ET:
It is possible to be diagnosed with ET and PMF without these mutations (triple-negative – negative for mutations in all three of JAK2, CALR and MPL) but this is very rare.
Types of tests
Different tests can be used to make a diagnosis:
| Results | What this means |
| MPL mutation is detected | If you have other clinical signs, then it is likely that you have ET and PMF. |
| No MPL mutations were detected | You may still have an MPN. The absence of this mutation makes it unlikely that you have ET and PMF, but the diagnosis has not been excluded. You could have a triple-negative MPN, or it could be that your MPL mutation was not detected during testing. |
| A bone marrow biopsy may be needed to decide which MPN you have and to assess its severity. | |
Treatments for MPL conditions
Your test results will show if your tissue sample is positive or negative for the MPL mutation – either MPL W515L or W515K mutation. This will help decide what treatment can be used to treat your symptoms and stop progression.
The greatest risk to your health and wellbeing from an MPN is the tendency for blood clotting. Managing an MPN condition is usually through low-dose aspirin taken to prevent blood clots.
Treatment is aimed at:
The treatment choice depends on your risk level, mainly based on your age and health history.
| Treatment management for MPNs | ||
| Risk level | Age | Treatment |
| Low risk | Younger than 60 No history of blood clotting disorders | Low dose aspirin Managing heart disease risk (e.g. blood pressure, cholesterol, glucose) |
| High risk | Older than 60 and/or history of blood clotting disorders | Aspirin
|
Questions to ask your doctor
The choice of tests your doctor makes will be based on your medical history and symptoms. It is important that you tell themeverything you think might help.
You play a central role in making sure your test results are accurate. Do everything you can to make sure the information you provide is correct and follow instructions closely.
Talk to your doctor about any medications you are taking. Find out if you need to fast or stop any particular foods or supplements. These may affect your results. Ask:
More information
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