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 JAK2?
JAK2 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, called haematopoietic stem cells, develop into different types of blood cells, including white blood cells, red blood cells and platelets. They 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 cells.
Receptors receive these chemical signals and transmit them to the nucleus at the centre of the cell, stimulating the cell to make more copies of itself.
The JAK2 gene makes a protein also called JAK2. This protein is part of 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. The JAK/STAT pathway relays growth signals from the receptor on the outside of the cell to the cell's nucleus telling the blood cell to copy itself and make new blood cells.
Normally, the JAK2 protein acts like a switch and only turns on when needed, then turns off again. When the JAK2 gene develops a mutation, a faulty JAK2 protein is made which keeps the switch stuck in the “on” position, sending constant "grow" signals to the blood cell.
What are myeloproliferative neoplasms (MPNs)?
A disorder in which too many blood cells are made is known as a myeloproliferative neoplasm (MPN). MPNs are an uncommon form of blood cancer. The three main MPNs are:
Polycythaemia vera (PV)
This is a condition in which bone marrow makes too many red blood cells. This makes the blood thicken. PV symptoms may be slow to appear, and it is often discovered during routine blood tests. Symptoms can include headaches, dizziness, itching and tingling or numbness.
Essential thrombocythaemia (ET)
This is a condition in which there are too many platelet-producing cells (megakaryocytes) made in the bone marrow. People with ET usually have no symptoms, but some may develop blood clots or bleeding because there are increased numbers of platelets made that may not function properly. Symptoms may include tingling in the hands and feet, headaches, dizziness, nosebleeds and easy bruising.
Primary myelofibrosis (PMF)
This is a condition in which there are too many platelet-producing cells and cells that produce scar tissue in the bone marrow. PMF is a serious disorder that leads to bone marrow scarring and can eventually turn into leukaemia. However, 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.
Other gene mutations found in MPNs
Mutations in other genes can cause MPNs. Mutations in the myeloproliferative leukaemia protein oncogene (MPL), and the calreticulin gene (CALR) have been associated with ET and PMF but are typically absent in PV.
JAK2 and BCR:ABL1
Genetic testing is also sometimes used to check for the Philadelphia (Ph') chromosome or a BCR:ABL1 translocation especially if it is possible you could have chronic myelogenous leukaemia (CML). A Ph’ chromosome and a BCR:ABL1 translocation refer to types of genetic changes where the chromosomes (the structures that genes are stored in) are altered when cells divide. MPNs almost never have both JAK2 mutation and BCR:ABL1 translocation at the same time and testing for the Ph' chromosome or a BCR:ABL1 translocation can help clarify your diagnosis.
Almost all JAK2 blood cancers are caused by somatic mutations
JAK2 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. Inherited (also called germline) JAK2 mutations do exist, but these are rare. They can increase a person's predisposition to developing MPNs. Your doctor will be able to tell if your mutation is somatic or germline based on your genetic testing results.
The JAK2 mutation test is used, along with other tests, to help diagnose bone marrow disorders. The test is typically ordered as a follow-up test if you have had a Full Blood Count which has shown a high haemoglobin level, white blood cell count and/or platelet count.
Mutation testing in the genes MPL and CALR may be ordered around the same time since mutations in MPL, CALR or JAK2 can lead to similar symptoms. These may be performed as single gene tests or as part of a panel of tests via Next Generation Sequencing (NGS).
JAK2 tests are performed on the genetic material found in the white blood cells called granulocytes, taken from either a blood or bone marrow sample, but not all granulocytes will have the JAK2 mutations. The proportion of affected cells will vary from person to person and may change over time. If there is only a small number in the blood sample tested, then it is possible that the mutation will not be detected.
Types of JAK2 mutations
Mutations can develop in different parts of the JAK2 gene. The JAK2 V617F mutation is the most common mutation. About 95 per cent of people with PV and about 50 per cent of people with ET or PMF will have this mutation. Up to five percent of people with PV have changes in another part of the JAK2 gene, called exon 12. More than 50 different locations where mutations occur have been identified but these are rare.
Types of tests
Different JAK2 genetic tests can be used to make a diagnosis:
| Results you may see on your report | What this means |
| The common JAK2 V617F mutation is detected | If you have other clinical signs, then it is likely that you have an MPN. |
| JAK2 V617F test is negative but the rarer JAK2 exon 12 mutation is detected | You do not have the common JAK2 mutation V617F, but you do have a different, rarer JAK2 mutation in exon 12. Both affect the same gene and can cause similar conditions. If you have other clinical signs, then it is likely that you have polycythaemia vera. |
| Very low-level JAK2 V617F mutations | These may be considered to be not clinically relevant. |
| No JAK2 mutations were detected | You may still have an MPN. The absence of the JAK2 mutation makes it unlikely that you have PV, but other MPNs have not been excluded. The absence of this mutation does not exclude diagnoses of ET or PMF. You could have a JAK2-negative MPN, or it could be that your JAK2 mutation was not detected during testing. |
| A bone marrow biopsy may be needed to decide which MPN you have and to assess its severity. | |
Monitoring
Some doctors may order a quantitative test periodically to monitor the change in the number of cells with the JAK2 V617F mutation over time.
Treatments for JAK2 conditions
Your test results will show if your sample is positive or negative for a JAK2 mutation – either JAK2 V617F or JAK2 exon 12. This will help decide what treatment can be used to treat your symptoms and stop progression.
The greatest risk from an MPN is blood clotting. Managing an MPN condition is usually through low-dose aspirin taken to prevent blood clots, and (in the case of PV) through the withdrawal of blood called venesection, in the same way a blood donation is performed, to reduce the number of blood cells. Medications such as hydroxycarbamide, interferon and ruxolitinib may also be used to reduce blood cell counts.
Treatment is aimed at:
The treatment choice depends on your risk level, and is mainly based on the type of MPN, your age and health history.
| Treatment management for MPNs | ||
| Risk level | Age | Treatment |
| Low risk | Younger than 60 No history of blood clotting disorders | Venesection 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 | Venesection & aspirin Cytoreductive therapy (lowers platelet count):
|
| Treatment resistance | If your blood cell counts are high and/or if you are having difficulty controlling your symptoms, despite taking hydroxyurea, or if you cannot tolerate it, you may be prescribed a JAK2 inhibitor such as Ruxolitinib, Fedratinib, Pacritinib or Momelotinib. JAK2 inhibitors work by blocking the faulty signalling caused by the JAK2 mutation. They act on the signalling pathways inside the cell. | |
The choice of tests your doctor makes will be based on your medical history and symptoms. It is important that you tell them everything 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:
Pathology and diagnostic imaging reports can be added to your My Health Record. You and your healthcare provider can now access your results whenever and wherever needed.
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