JAK2 Mutation

The JAK2 mutation test may be used, along with other tests such as CALR mutation and MPL mutation testing, to help diagnose bone marrow disorders that lead to the production of too many blood cells. These disorders are known as myeloproliferative neoplasms (MPNs).

The JAK2 mutation test is typically ordered as a follow-up test if a person has a significantly increased hemoglobin, hematocrit, red blood cells and/or platelet count and the healthcare practitioner suspects that the person may have an MPN, especially polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF).

The primary genetic test for JAK2 mutations that lead to MPNs is JAK2 V617F, named for a mutation at a specific location in the JAK2 gene. It is typically ordered first. If it is negative, then tests for other mutations in the JAK2 gene that are also associated with MPNs, such as JAK2 exon 12, may be used to help make a diagnosis.

The JAK2 V617F test may be ordered along with other tests when a healthcare practitioner suspects that a person has a myeloproliferative neoplasm (MPN). Testing may be done when routine laboratory test results, such as from a complete blood count (CBC), reveal abnormal results associated with these MPNs.

Sometimes people with MPNs may have no symptoms or a few, relatively mild ones that may be present for years before being recognized as an MPN, often during a routine physical. However, a healthcare practitioner may suspect an MPN and order testing when a person has, for example:

• Enlarged spleen (splenomegaly) or liver (hepatomegaly)
• A blood clot in a vein or artery
• Heart attack
• Stroke or transient ischemic attack
• Bleeding
• Headache
• Dizziness
• Vision problems
• Numbness
• Itchiness
• Gout
• Kidney stones
• Fatigue
• Shortness of breath
• Weight loss
• Fever

The JAK2 exon 12 test and/or a test for other non-V617F JAK2 mutations may be ordered when the JAK2 V617F test is negative and the healthcare practitioner still suspects polycythemia vera.

A positive JAK2 V617F mutation test, along with other supporting clinical signs, means it is likely that the person tested 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.

More than 95% of people with polycythemia vera (PV) and 50-60% of people with essential thrombocythemia (ET) or primary myelofibrosis (PMF) have a JAK2 mutation, most for the JAK2 V617F mutation. Additionally, the mutation is also rarely found in people with chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myeloid leukemia (CML).

A negative JAK2 V617F test but a positive JAK2 exon 12 mutation or other non-V617F mutation test along with supporting clinical signs means it is likely that the person has polycythemia vera. About 3-4% of people with PV have an exon 12 mutation.

Negative results for all JAK2 mutations does not necessarily rule out an MPN—the person may have a JAK2-negative MPN or the JAK2 mutation was not detected during testing. The JAK2 tests are performed on the genetic material found in white blood cells called granulocytes (from blood or bone marrow) and red cell precursors (from bone marrow). 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 of cells that have the mutation in the blood sample tested, then it is possible that the mutation will not be detected.

In 2016, the World Health Organization (WHO) revised its diagnostic criteria for PV and ET. The presence of a JAK2 V617F or JAK2 exon 12 mutation is one of three major criteria listed for diagnosis of PV. However, consensus has not yet been achieved for the optimal diagnostic criteria for PV.

The finding of a JAK2 mutation associated with uncontrolled blood cell growth in MPN also suggests a possible therapeutic approach to some MPNs. As an example, one JAK2 inhibitor has been approved for the treatment of intermediate and high-risk myelofibrosis.

A few laboratories offer both a JAK2 V617F test that detects the mutation (qualitative) and a test that measures how many of cells in the sample have the mutation (quantitative). Some healthcare practitioners may order 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.