What Is a JAK2 Mutation?

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The Janus kinase 2 (JAK2) gene directs cells to make the JAK2 protein, which stimulates cell growth and division. The JAK2 protein is particularly important for controlling blood cell production from hematopoietic (blood-forming) stem cells.

These stem cells are located in the bone marrow (the spongy tissue inside the bones) and have the ability to develop into new blood cells. Blood cells include red blood cells (carry oxygen to tissues), white blood cells (fight infections), and platelets (help clot blood to stop bleeding).

While JAK2 mutations are rare, they can cause various bone marrow disorders. These are known as myeloproliferative neoplasms (MPNs), where the bone marrow produces too many blood cells.

This article highlights the causes of JAK2 mutations and the common disorders they cause.

Blood cells under a microcope. JAK2 mutations can increase blood cell production

Dr_Microbe / Getty Images

Causes

The most common JAK2 mutation found in blood disorders is known as JAK2 V617F, named for a mutation at a specific location in the JAK2 gene.

Rather than being inherited, JAK2 V617F mutations are acquired, occurring at random. As they occur in cells that do not produce eggs or sperm, the mutation is not passed on to a person's children.

The mutation is a point mutation, replacing the normal amino acid valine (V) with phenylalanine (F) in the DNA of one gene. This causes the JAK2 protein to be constantly switched "on," leading to uncontrolled blood cell production.

Prevalence of JAK2 V617F Mutations

The prevalence JAK2 V617F proteins in the general population is about 0.2%. However, JAK2 V617F mutations are present in 95% of cases of polycythemia vera (PV).

Myeloproliferative Neoplasms (MPNs)

Myeloproliferative neoplasms occur when blood stem cells produce too many of one or more types of blood cells, including red blood cells, white blood cells, and platelets. The effects of these neoplasms (abnormal growth of cells) slowly worsen as the number of extra blood cells increases.

MPNs commonly associated with JAK2 mutations include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).

Polycythemia Vera (PV)

Polycythemia vera (PV) is a rare blood disorder where the bone marrow makes too many blood cells. The increase in blood cells makes your blood thicker, which can lead to an increase in blood clots. This can cause strokes or tissue and organ damage.

Common symptoms of PV include fatigue or weakness, headaches, dizziness, shortness of breath, visual disturbances, nose bleeds, night sweats, and more. Treatments may include medicines, such as chemotherapy, to control the number of RBCs produced, and phlebotomy (a procedure that removes extra blood from the body).

Essential Thrombocythemia (ET)

Essential thrombocythemia (ET) is a disorder in which there are too many platelet-producing cells (megakaryocytes) in the bone marrow. While the exact cause of ET is unknown, over half of all ET patients have a JAK2 gene mutation in their blood-forming cells.

Risk factors associated with ET include gender and age. It occurs in females 1.5 times more often than in males. It's more common in people older than 60, but one-fifth of people with ET are under 40.

There may be no symptoms with ET and instead, it is found on routine blood tests. If there are symptoms, they are due to the effects of clotting in small blood vessels or bleeding. There can also be complications of major clotting events, such as a stroke or heart attack.

Treatments for ET vary depending on a person's symptoms. These include:

  • Low-dose aspirin: This reduces the risk of blood clot formation.
  • Platelet-lowering medications: Droxia or Hydrea (hydroxyurea), Agrylin (anagrelide), or interferon-alpha lower the number of platelets, reducing the risk of bleeding or clotting.
  • Plateletpheresis: This procedure can quickly lower your platelet count following a stroke or clotting incident. Plateletpheresis involves removing blood through an intravenous line, separating and removing the platelets, and returning the rest of the blood components through another line.

Primary Myelofibrosis (PMF)

Primary myelofibrosis (PMF) is a rare bone marrow cancer caused by the formation of too many cells that produce platelets and granulocytes (a type of white blood cell). This leads to chronic inflammation and the replacement of bone marrow with fibrous (scar) tissue.

The disorder develops when a mutation occurs in the DNA of a single hematopoietic stem cell. When mutated blood cells replicate and divide, they pass the mutation to new cells. Eventually, abnormal cells overtake the bone marrow's ability to produce enough blood cells.

Risk factors of PMF include age and environment. People are most often over 60 at diagnosis, but it can affect those younger. Exposure to petrochemicals like benzene and toluene may also increase the risk of developing the disease.

Common treatments of PMF include:

JAK inhibitors are used to reduce the activity of JAK family genes. Inrebic (fedratinib) inhibits JAK2, and Jakafi (ruxolitinib) partially inhibits JAK2 and JAK1. These medications can also ease some common symptoms of the disease, including an enlarged spleen, bone pain, night sweats, and more.

However, side effects, like decreased platelets or worsening anemia, have been reported. You may also experience bruising, dizziness, or headaches.

Allogenic stem cell transplantation (ASCT) replaces defective stem cells with healthy ones from a donor. Chemotherapy or radiation is first given to kill the abnormal stem cells in the recipient's bone marrow.

The new stem cells are given by infusion and move through the bloodstream to the bone marrow, where they will begin to grow and produce new blood cells. This is known as engraftment.

Summary

The Janus kinase 2 (JAK2) gene directs cells to make the JAK2 protein, which promotes cell growth and division. The JAK2 protein is important for controlling blood cell production from hematopoietic (blood-forming) stem cells.

The most common JAK2 mutation associated with blood disorders is JAK2 V617F. It causes JAK2 protein production to be constantly switched "on," leading to uncontrolled blood cell production.

Myeloproliferative neoplasms (MPNs) occur when blood stem cells produce too many of one or more types of blood cells. Treatments differ based on the type of MPN a person has. MPNs most commonly associated with JAK2 mutations include polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

A Word From Verywell

While JAK2 mutations are rare, they can be life-changing for you and your loved ones. It can also be frightening and stressful. While PV and ET are generally less aggressive disorders, they may develop into PMF, which is considered a blood cancer and is more aggressive.

If you have symptoms consistent with MPNs or are diagnosed with a blood disorder, speak to your healthcare provider about treatment options that are optimal for you. Early detection of MPNs is essential to avoid progressing to a more aggressive form.

In addition to clinical treatment, keep up a good daily health regime. This may include creating a healthy diet plan with a dietitian, exercising, getting enough rest, or joining a support group.

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10 Sources
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