JAK2

JAK2 (Janus kinase 2) is a gene that provides instructions for making a protein involved in how cells grow, divide, and respond to signals from the immune system. JAK2 is part of a family of related genes that also includes JAK1, JAK3, and TYK2. These genes all produce proteins that help cells communicate using a pathway known as JAK-STAT, which is especially important in blood cell development and immune system function.

What does JAK2 do?

The protein made by the JAK2 gene is called a tyrosine kinase, which acts like a switch inside cells. When specific signals (like hormones or growth factors) bind to receptors on the cell surface, JAK2 helps send those signals into the cell. This activates a chain of events that controls how the cell behaves, including its growth, survival, and performance of its specific functions. In particular, JAK2 is crucial for the formation of blood cells in the bone marrow.

Where is JAK2 normally found or active?

JAK2 is active in many types of cells throughout the body, particularly in cells that respond to signals from hormones and immune system proteins known as cytokines. It is most active in blood-forming tissues such as the bone marrow, where it helps regulate the production of red blood cells, white blood cells, and platelets. It also plays a role in the immune system by helping cells respond to infections and inflammation.

Why is JAK2 important in disease?

Changes (mutations) in the JAK2 gene can cause the protein to become permanently active, even without receiving a signal. This leads to uncontrolled cell growth, which can result in certain types of blood cancers called myeloproliferative neoplasms (MPNs). The most common mutation is called JAK2 V617F, and it is found in:

• Over 95% of people with polycythemia vera (PV).

• About 50–60% of people with essential thrombocythemia (ET) or primary myelofibrosis (PMF).

Other JAK2 mutations can also be found in chronic eosinophilic leukemia, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), and some solid tumors such as lung or breast cancer. These mutations help doctors diagnose these diseases and may influence treatment choices. JAK2 abnormalities can also occur in noncancerous conditions characterized by abnormal blood counts or inflammation.

How do pathologists test for JAK2?

Pathologists test for changes in the JAK2 gene using specialized laboratory techniques known as molecular tests. These tests look for genetic mutations (changes in the DNA sequence) that can cause the JAK2 protein to become abnormally active. Testing is most often performed on a sample of blood or bone marrow. Here are the most common testing methods:

Polymerase Chain Reaction (PCR)

PCR is a highly sensitive technique used to detect specific, known mutations—most commonly the JAK2 V617F mutation. In this test, the DNA from your sample is amplified, allowing for the identification of small amounts of mutated DNA.

• Example result: “JAK2 V617F mutation detected (allele burden: 35%)”
  This means the mutation was found in 35% of the tested cells, which may reflect the proportion of abnormal cells in the sample.

• If the mutation is not found, the report might say: “JAK2 V617F mutation not detected.”

Next-Generation Sequencing (NGS)

NGS is a broader test that analyzes many genes at once, including all parts (exons) of the JAK2 gene. It can detect rare or complex mutations beyond V617F, such as those in exon 12, which are important for diagnosing polycythemia vera in patients who test negative for V617F.

• Example result: “JAK2 exon 12 mutation detected: c.1614_1616del (p.H538_K539delinsL)”
  This means a deletion and insertion was found in exon 12, which can be associated with polycythemia vera.

• If no mutations are found in the gene, the report might say: “No pathogenic variants detected in JAK2.”

Allele-Specific PCR (also called ASO-PCR or ARMS)

This highly sensitive version of PCR is used to detect very small amounts of mutated DNA, such as in patients receiving treatment or in remission (minimal residual disease). It is typically used when the mutation is already known.

• Example result: “Low-level JAK2 V617F mutation detected (allele burden: 0.5%)—below the limit of detection for standard PCR.”
  This suggests a small number of abnormal cells remain.

Fluorescence In Situ Hybridization (FISH)

FISH uses fluorescent probes to detect structural changes in the chromosome, such as JAK2 rearrangements or translocations. This is especially useful in certain rare blood cancers that involve gene fusions (e.g., PCM1::JAK2).

• Example result: “Abnormal JAK2 rearrangement detected by FISH using break-apart probes.”

• If the result is normal: “No evidence of JAK2 rearrangement by FISH.”

RNA-based fusion testing

This test looks for fusion genes involving JAK2 using RNA extracted from the sample. Fusion genes occur when part of the JAK2 gene becomes joined to another gene, which can drive cancer growth. This is often done using RNA-based next-generation sequencing.

• Example result: “Fusion transcript detected: PCM1::JAK2”
  This finding may support the diagnosis of a rare myeloid or lymphoid neoplasm with a JAK2 rearrangement.

Together, these tests help pathologists identify the presence, type, and extent of JAK2 mutations, which are essential for making an accurate diagnosis, guiding treatment decisions, and monitoring disease progression or response to therapy. Your pathology report may include one or more of these methods depending on your diagnosis and clinical situation.

Questions to ask your doctor

• What does my JAK2 test result mean?

• Do I have a JAK2 mutation, and if so, which one?

• Does my diagnosis include a myeloproliferative neoplasm or another type of blood disorder?

• Could JAK2 testing help guide my treatment?

• Am I a candidate for targeted therapy with a JAK inhibitor?

• Will my JAK2 mutation affect my prognosis or risk of progression?