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Myeloproliferative neoplasms (MPNs) are a subset of bone marrow disorders. They are a group of four diseases characterised by an overproduction of one or more types of blood or fibre cells in the bone marrow. Bone marrow is a soft fatty tissue that is located in the centre of the body's larger bones. It contains a fibrous network, a population of undifferentiated pluripotent , and a mixture of red blood cells (RBC), white blood cells (WBC), and platelets in various stages of maturity.
Normally, the body maintains a dynamic but relatively stable number of blood cells in circulation. As cells age, die, or are removed from circulation, new ones are made in the marrow to replace them. When a particular kind of blood cell is needed, some of the stem cells in the bone marrow begin to change, becoming the immature ‘blast’ forms of whatever cell type is in short supply. These blasts mature to become white blood cells, red blood cells or platelets. Usually only fully mature cells are released into circulation.
With an MPN, excessive production of a cell’s precursor leads to an increased number of that type of mature cell and to a corresponding increase or decrease in the number of other blood cells, which may be inhibited and crowded out. This results in symptoms related to blood cell overproduction, shortages and dysfunction throughout the body.
The actual genetic event that leads to the development of several MPNs has been studied. Doctors can use the measurement of these abnormal genes or the proteins they produce to diagnose and measure the effectiveness of treatment. These measurements are done by very specialized molecular techniques and generally only available from specialised laboratories. Your doctor may have to send your blood or bone marrow sample away to a special laboratory for the results.
The diseases included in the group of MPN are:
- Chronic myelogenous (myeloid) leukaemia (CML), a disease that leads to an overproduction of myelocytes, precursor to granulocytes - white blood cells that digest and kill invading . Often, these overproduced cells do not function normally. CML is rare in children. It is an acquired condition that begins in an immature in the bone marrow when pieces from two chromosomes (9 and 22) break off and switch places (translocation). This results in an altered, fused gene (BCR/ABL) on chromosome 22, the ABL gene from chromosome 9 and the BCR gene from chromosome 21. The abnormal chromosome is labelled t(9;21)(q34;q11) which describes the chromosomes from which is arises (9 and 21) and the part of the chromosome where the break and translocation occurs (q34 and q11). It is also known as the Philadelphia chromosome. The BCR-ABL fusion gene produces copies of the BCR-ABL gene and proteins with abnormal tyrosine kinase activity that affect cell growth and regulation. This leads to an overproduction of granulocytic white blood cells, many with the BCR/ABL translocation, and the presence of both mature and immature cells in the bloodstream. Diagnosis is suspected when a pathologist looks at a patient’s peripheral blood which has a characteristic mix of mature and immature granulocytes. The diagnosis is confirmed by identifying and measuring the Philadelphia chromosome or the BCR/ABL gene in the blood or bone marrow and examining the bone marrow. Treatment is now available with a specialised small molecule drugs called tyrosine kinase inhibitor which bind specifically to the BCR-ABL tyrosine kinase and stop it working. Imatinib (also known by its trade name as Glivec®) is the drug that most patients are started on when they are diagnosed with CML. Measurements of the BCR/ABL gene with a blood test are used to monitor the effectiveness of therapy.
- Polycythaemia vera (PV), a disease in which too many red blood cell precursors and erythrocytes (red blood cells) are made in the bone marrow. The increased production of red blood cells occurs independently of the body's usual control mechanisms. Almost all PV cases have a mutation of the Janus 2 kinase gene (JAK2 mutation) at a particular point in the gene labelled V617F. JAK2 is a tyrosine kinase, when the V617F mutation occurs its activity does not switch off normally and production of red cells increases unchecked. When RBCs build up in the blood stream, they can cause the to swell. Itchiness occurs, especially in warm water and there may be changes in the skin colour. The most serious problem is the excess red blood cells can make the blood thicker, which can increase the risk of inappropriate clotting (thrombosis) in both the veins and arteries. This may result in a stroke or clots causing damage to vessels and important organs of the body. Polycythaemia vera is also called primary polycythaemia. A variety of other factors can cause increased red blood cell production; for instance, long-term exposure to low concentrations of oxygen. These increases in RBCs are referred to as secondary polycythaemia. Diagnosis is usually made following a routine examination where an increase in red blood cells (polycythaemia) or haemoglobin is found. The patient’s medical history is checked and other investigations may be performed to distinguish between primary and secondary polycythaemia. The JAK2V617F mutation can be looked for in the peripheral blood and a bone marrow biopsy is usually required to complete the diagnosis. Management is aimed at reducing the red cell volume and the risk of thrombosis. In the first instance this is usually done by the patient donating blood (venesection) and the use of aspirin if there are no contraindications.
- Essential thrombocythaemia (ET), characterised by an increased number of megakaryocytes, precursor to platelets. About half (50%) of ET cases have the mutation of the Janus 2 kinase gene, JAK2V617F. Platelets change shape and become ‘sticky’ during the clotting process. This characteristic allows them to plug holes in leaking blood vessels, but excess platelets and platelet clumping can make it hard for the blood to flow normally and can increase a person’s risk of developing inappropriate blood clots, a stroke or heart disease. Diagnosis is made by firstly distinguishing ET from secondary thrombocytosis – increased numbers of platelets caused by non-marrow disorders such as iron deficiency, rheumatoid arthritis, bleeding or removal of the spleen. The JAK2V617F mutation can be looked for in the peripheral blood cells and a bone marrow biopsy is usually required to complete the diagnosis. Management of ET is aimed at reducing the risk of the disease. This includes ensuring that patients have their cardiovascular risk factors managed including blood pressure management, stopping smoking, cholesterol control and preventing or managing weight problems and diabetes. Aspirin is usually recommended if there are no contraindications. Tablet based chemotherapy to reduce the platelet count may be used in some patients.
- Primary myelofibrosis (PMF) is a disease characterised by overproduction of megakaryocytes (platelet precursors) and precursors of mature red blood cells and white blood cells in the bone marrow. In the fully developed disease this is also associated with deposits of fibrous connective tissue in the bone marrow. About half (50%) of PMF cases have the mutation of the Janus 2 kinase gene, JAK2V617F. The dense network of fibre inhibits the normal formation and maturation of RBCs and myelocytes. The red blood cells that do enter the bloodstream are often malformed, looking like teardrops instead of circles. There may be too few normal mature red blood cells to carry oxygen, causing anaemia. Fibre cells may also spread to the spleen. The spleen and liver may become enlarged as a result. A bone marrow biopsy is required to diagnose PMF. Management of PMF includes support with transfusions of red blood cells and in younger patients consideration for a bone marrow transplant from a donor (often a relative).
- Other rare disorders: chronic neutrophilic leukaemia; some types of chronic eosinophilic leukaemias and mastocytosis.
MPNs are not curable, but their slow progression can usually be controlled and their symptoms alleviated. For each, there is a slight chance that the disease will develop into an acute leukaemia. If this occurs, the course of the disease will be accelerated, the symptoms will intensify, and more aggressive treatment will be required.
Last Review Date: January 13, 2020