JAK2 Mutation

The JAK2 mutation test may be used, along with other tests such as erythropoietin, to help diagnose bone marrow disorders that lead to overproduction of blood cells. These conditions are known as myeloproliferative neoplasms (MPNs).

The MPNs most commonly associated with JAK2 mutation are: polycythaemia vera (PV), where bone marrow makes too many red blood cells; essential thrombocythaemia (ET), where there are too many platelet-producing cells in the bone marrow; and primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis or agnogenic myeloid metaplasia, where there are too many platelet-producing cells and cells that produce scar tissue in the bone marrow. The JAK2 mutation test is typically requested as a follow-up test if a person has a significantly increased haemoglobin and/or platelet count and the healthcare professional suspects that the person may have an MPN.

JAK2 V617F is named for a mutation at a specific location in the JAK2 gene and is the primary genetic test for JAK2 mutations that lead to MPNs. JAK2 mutations are acquired as opposed to inherited and result in the change of a single DNA nucleotide base pair, called a point mutation. This change results in a JAK2 protein that is constantly "on," leading to uncontrolled blood cell growth.

Mutations in other coding portions (called exons; they code for protein) of the JAK2 gene are also associated with MPNs. There is a test also available to detect changes in JAK2 exon 12. Two to five percent of people with PV have an exon 12 mutation.

The presence of a JAK2 mutation helps a healthcare professional make a definitive diagnosis of MPN (PV, ET or PMF), but the absence of a JAK2 mutation does not rule out MPN. In 2008, the World Health Organization (WHO) revised its diagnostic criteria for PV and ET, adding the presence of JAK2 mutation as a criterion. The finding of a JAK2 mutation associated with uncontrolled blood cell growth in MPN also suggests a possible therapeutic approach to some MPN. As an example, one JAK2 inhibitor has been approved for the treatment of intermediate and high risk myelofibrosis.

The JAK2 V617F test may be requested along with other tests when a healthcare professional suspects that a person has a blood disorder known as a myeloproliferative neoplasm (MPN), especially polycythaemia vera (PV), essential thrombocythaemia (ET), or primary myelofibrosis (PMF). Many routine laboratory results such as a full blood count (FBC) reveal abnormal results associated with these MPNs, and someone may also have signs and symptoms that suggest an MPN.

Sometimes people with MPNs may have no symptoms or a few, relatively mild ones that may be present for years before being recognised as an MPN, often during a routine health check. However, if certain signs and symptoms appear, a health care provider may suspect that someone has one of these MPNs. They have many signs and symptoms in common, for example:

• Weakness and fatigue
• Shortness of breath during exertion
• Loss of appetite and weight loss
• Enlarged spleen (splenomegaly)
• Bleeding and bruising, due to low and/or abnormal platelets
• Night sweats
• Bone and joint pain
• A pale appearance due to anaemia (when red blood cells are decreased)
• Frequent infections

Polycythaemia vera (PV) may also be suspected when symptoms such as headaches, dizziness, visual distortion, itching and paresthesia (abnormal skin sensation, such as tickling, tingling or numbness) appear. In PV, there are an excess number of red blood cells and the resulting blood thickening may lead to complications such as stomach ulcers, kidney stones, venous thrombosis, stroke, and rarely to congestive heart failure. Since PV symptoms may be slow to appear, it is often discovered during routine blood tests.

Those with essential thrombocythaemia (ET) usually have no symptoms, but some may develop inappropriate blood clots (thrombosis) or bleeding (haemorrhage) because there are increased numbers of platelets produced that may not function properly. A blood clot could also cause a temporary interruption of blood flow to part of the brain (a transient ischemic attack) or stroke. Other symptoms from blood clots or excessive bleeding may include tingling in the hands and feet, headaches, dizziness, nosebleeds, and easy bruising.

Primary myelofibrosis (PMF) is a serious disorder that leads to bone marrow scarring and can eventually evolve into other, more serious forms of leukaemia. However, some people with PMF have no symptoms for years. People who do have symptoms may have those that are associated with severe anaemia, such as fatigue and weakness. A JAK2 mutation test may be done if routine laboratory tests suggest PMF.

The JAK2 exon 12 test may be requested when the JAK2 V617F test is negative and the doctor still suspects PV. 

If the JAK2 V617F mutation is detected and the person has other supporting clinical signs, then it is likely that the person has an MPN. Other testing, such as a bone marrow biopsy, may need to be performed to determine which MPN the person has and to evaluate its severity.

If the JAK2 V617F test is negative but a JAK2 exon 12 mutation is detected and the person has supporting clinical signs, then it is likely that the person has polycythaemia vera.

If the person is negative for all JAK2 mutations, the person may still have an MPN. The person could have a JAK2-negative MPN or their JAK2 mutation was not detected during testing. The JAK2 tests are performed on the genetic material found in granulocytes (from blood or bone marrow) and red cell precursors (from bone marrow), but not all granulocytes and red cell precursors will possess 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.

The presence of other mutations can help confirm the diagnosis of an MPN. Recently, mutations in the CALR (calreticulin) gene have been associated with 30-40% of JAK2-negative MPNs. Mutations in MPL account for 5% of JAK2-negative MPNs.

A few laboratories are offering both qualitative and quantitative JAK2 V617F tests. Some healthcare professionals may request a quantitative test to monitor the change in the number of cells with the JAK2 V617F mutation over time. However, the quantitative test is not performed commonly as a standard practice and its clinical utility has yet to be strongly established.

JAK2 mutation testing must be performed in a laboratory that performs molecular testing. It is not offered by every laboratory and must often be sent out to a reference laboratory.