Like all cancers, myeloproliferative neoplasms (MPNs) develop due to mutations, or changes, in genes that tell the body how to make proteins. One of the most commonly mutated proteins found in MPNs is the Janus kinase 2 (JAK2) protein.

The discovery of JAK2 changed how doctors diagnose and treat people with MPNs, providing new options for people with this mutation. We’ll discuss how the JAK2 gene and protein are related to MPNs and how they can be targeted to treat blood cancer.

Mutations and Myeloproliferative Neoplasms

Gene mutations that lead to cancer are usually acquired over a person’s lifetime rather than inherited from parents. Mutated genes tell the body to make abnormal proteins or too many proteins, or they might shut down production of a protein. If these changes cause abnormal growth of cells, they may result in cancer.

MPNs are blood cancers caused by the overproduction of blood cells in the bone marrow. Mutations in the gene controlling JAK2 protein production occur most often in the three classic types of MPNs:

• Polycythemia vera — Overproduction of red blood cells
• Essential thrombocythemia — Overproduction of platelets
• Primary myelofibrosis — Buildup of scar tissue in the bone marrow, inhibiting the production of new blood cells

The V617F mutation in the JAK2 gene is found in:

• 96 percent of polycythemia vera cases
• 50 percent to 60 percent of primary myelofibrosis cases
• 50 percent to 60 percent of essential thrombocythemia cases

Additionally, more than 50 different mutations have been found in other parts of the JAK2 gene, primarily in polycythemia vera cases.

What Is the JAK2 Gene?

The JAK2 protein plays an important role in controlling the production of blood cells from stem cells found in the bone marrow.

The JAK2 gene is responsible for genetically coding the JAK2 protein. This protein is part of the JAK/STAT pathway, which transmits signals to promote cell growth.

When the JAK2 protein is activated, it relays a signal to the protein STAT, which then binds to another STAT molecule in a process called dimerization. This group of molecules then moves into the cell’s nucleus, turning on genes that tell the cell to grow and proliferate. This process of cell production is normally well regulated in the body. However, any mutation in the JAK/STAT system will lead to uncontrolled cell production and an excess of blood cells.

What Causes JAK2 Mutations?

Two main types of JAK2 mutations are found in MPNs.

V617F Mutation

The V617F mutation is caused by a change in a single base in the genetic code. This simple change then switches the amino acid valine (V) to phenylalanine (F) at position 617 in the JAK2 protein, altering the protein’s shape. When this mutation is present, JAK2 signaling gets turned on and can’t be turned off, and cells grow uncontrolled. In the case of MPNs, this causes an overproduction of blood cells, leading to blood cancers.

Multiple Mutations

Many types of mutations can be found within multiple parts of the JAK2 gene. More than 50 different mutations have been identified in the gene, and almost all of them occur in people with polycythemia vera.

One part of the JAK2 gene is particularly susceptible to mutations. This area genetically codes for a linker that connects two parts of the JAK2 protein. Common mutations here include deletions and insertions. A deletion occurs when entire pieces of the protein are lost. An insertion happens when incorrect pieces are put into the protein. Insertions and deletions change the shape of the JAK2 protein, which can affect its function.

Do JAK2 Mutations Cause Myeloproliferative Neoplasms?

MPNs are caused by a mutation in a single stem cell found in the bone marrow. These mutations cause the cell to rapidly divide, producing too many of one cell type. JAK2 gene mutations are involved in many cases of MPNs. In addition to JAK2 genes, CALR and MPL genes also contain mutations and are common contributors to the development of MPNs. These three mutations are usually mutually exclusive, meaning that if one mutation is present, then the others are not.

JAK2 Mutations and MPN Diagnosis and Prognosis

A number of tests are required to diagnose MPNs, each providing a different piece of information. Your doctor will begin with a physical examination and health history. They may also order a complete blood count with a differential, which assesses the number of red blood cells, platelets, and white blood cells. You may also need to get a bone marrow biopsy to provide bone marrow samples for testing.

Because most MPNs are associated with a specific genetic mutation, a pathologist may use blood samples to test for these. Two tests that help identify genetic abnormalities are quantitative polymerase chain reaction (qPCR) and fluorescent in situ hybridization (FISH). Typically, just one of these tests is required for diagnosis. DNA sequencing may also be done to identify the driving mutation.

Quantitative Polymerase Chain Reaction

Most often, qPCR is used for diagnosing JAK2 mutations. This is also the most sensitive test, and it can detect small amounts of mutation when other methods fail.

With qPCR, DNA obtained from a blood test is mixed with a fluorescent dye, which is run through a machine that amplifies the sequences containing the JAK2 mutation. This test is also repeated over the course of treatment to see if the quantity of the mutated gene has reduced over time, indicating a good response to therapy.

Fluorescent In Situ Hybridization

FISH testing determines whether someone has chromosomal abnormalities contributing to a cancerous phenotype (observable characteristics). This test can identify mutations by using probes, which are marked with a fluorescent dye, to search for and attach to the chromosomes of corresponding tumor cells — a process called hybridization. FISH tests can be performed on samples from blood or bone marrow.

In 2022, the World Health Organization (WHO) revised the document “WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues.” The revision includes new criteria for diagnosing MPNs by the three main driver mutations in JAK2, CALR, and MPL genes. Polycythemia vera is characterized by the presence of a JAK2 mutation. Essential thrombocythemia and primary myelofibrosis are characterized by the presence of any of the three driver mutations.

JAK2 Mutations and MPN Treatments

Since the discovery of JAK2 mutations in MPNs, researchers have developed a number of JAK2 inhibitors — therapies that target the JAK2 protein. The U.S. Food and Drug Administration (FDA) has approved four JAK2 inhibitors for the treatment of MPNs, which are discussed below.

Ruxolitinib (Jakafi)

Ruxolitinib (Jakafi), the first JAK2 inhibitor to receive FDA approval for the treatment of MPNs, is approved for treatment of intermediate- and high-risk myelofibrosis. This includes primary myelofibrosis, as well as post-polycythemia vera and post-essential thrombocythemia myelofibrosis. Additionally, some trials are investigating the effects of combining ruxolitinib with the antimetabolite chemotherapies azacitidine (Vidaza) and decitabine (Dacogen). Antimetabolites are cancer drugs that interfere with DNA by acting as a substitute for the normal building blocks of DNA.

Fedratinib (Inrebic)

Fedratinib (Inrebic) was approved in 2019 for treating three forms of myelofibrosis: high-risk, post-polycythemia vera, and post-essential thrombocythemia with splenomegaly (enlarged spleen). In this context, risk refers to the chances that myelofibrosis will transform into a more aggressive form of blood cancer such as acute myeloid leukemia, or AML.

Pacritinib (Vonjo)

Pacritinib (Vonjo) received FDA approval in February 2022. It’s used for the treatment of intermediate- and high-risk primary and secondary (post-polycythemia vera and post-essential thrombocythemia) myelofibrosis in people with severe thrombocytopenia (low blood platelet counts), which can be a side effect of ruxolitinib or fedratinib.

Momelotinib (Ojjaara)

Momelotinib (Ojjaara) was approved in 2023 to treat adults with intermediate- or high-risk myelofibrosis who are experiencing anemia (low hemoglobin levels), a possible side effect of ruxolitinib or fedratinib. Momelotinib may be recommended for people who have primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis.

Overall, the discovery of JAK2 mutations in MPNs has helped advance drug research, development, and treatment. Research into these drugs has also provided new ways to combat uncontrolled proliferation of blood cells, improving the lives of people with MPNs. New medications continue to be developed and tested, providing a hopeful future for those affected by myeloproliferative diseases.

Read more about how MPN research leads to new treatments that improve lives.

Finding Support if You Have a Myeloproliferative Neoplasm

You are not alone living with an MPN. When you join myMPNteam, you gain a community of others who know what it’s like to face a rare blood cancer diagnosis.

Do you know whether your MPN cells have tested positive for a JAK mutation? Did your doctor explain what the results of the test mean for your condition? Share your experiences in a comment below or post on your Activities page.