What is a myeloproliferative neoplasm?

A myeloproliferative neoplasm is a group of blood cancers that start in the bone marrow, the soft tissue inside your bones where new blood cells are made. In these conditions, the bone marrow produces too many mature blood cells. The extra cells may be red blood cells, white blood cells, or platelets, depending on the specific type of myeloproliferative neoplasm.

Myeloproliferative neoplasms are different from myelodysplastic neoplasms because the blood cells in myeloproliferative neoplasms look normal under the microscope. Most people are diagnosed in a “chronic phase,” meaning the disease is stable and growing slowly.

Where are myeloproliferative neoplasms commonly found?

Myeloproliferative neoplasms involve the blood and bone marrow. They are usually found after routine blood tests show elevated red blood cell, white blood cell, or platelet counts. A bone marrow biopsy is often performed to confirm the diagnosis. Genetic testing is also important because most myeloproliferative neoplasms carry specific gene changes (mutations) that help guide diagnosis.

What are the most common types of myeloproliferative neoplasms?

There are several diseases within the myeloproliferative neoplasm category. Each type is defined by which blood cell line is overproducing and by specific genetic features. Most people are diagnosed in the chronic phase, when the disease behaves slowly, and symptoms may be mild.

The main types include:

• Polycythaemia vera (PV): PV causes the bone marrow to make too many red blood cells. Some people also have elevated white blood cell or platelet counts. Common symptoms include headaches, itching after warm showers, and a feeling of fullness in the abdomen due to an enlarged spleen.
• Essential thrombocythaemia (ET): ET causes an excess of platelets in the blood. Many people feel well, but some experience headaches, redness or burning in the hands and feet, or an increased risk of blood clots.
• Primary myelofibrosis (PMF): PMF causes abnormal growth of megakaryocytes, the cells that make platelets. These cells release signals that lead to scarring (fibrosis) in the bone marrow. Over time, the bone marrow may struggle to make blood cells normally, leading to anemia and an enlarged spleen.
• Chronic myeloid leukemia (CML): CML is caused by the BCR::ABL1 fusion gene, which creates an abnormal protein that drives the uncontrolled growth of white blood cells. Modern targeted treatments are very effective, and many people live long, stable lives with this condition.
• Chronic eosinophilic leukemia (CEL): CEL causes an excess of eosinophils, a type of white blood cell involved in allergic reactions and in fighting parasites. Symptoms may include fatigue, cough, or effects on organs such as the heart or skin.
• Juvenile myelomonocytic leukemia (JMML): JMML is a rare MPN that occurs in children. It causes an excess of monocytes, a type of white blood cell. JMML is strongly linked to changes in genes that regulate RAS signaling.
• Myeloproliferative neoplasm, not otherwise specified (MPN-NOS): This diagnosis is used when a patient clearly has a myeloproliferative neoplasm but does not meet the full criteria for any specific type. This may happen when features overlap across diseases.

What are the disease phases in a myeloproliferative neoplasm?

Most myeloproliferative neoplasms begin in a chronic phase, where the disease grows slowly. Some may progress into more advanced stages.

• Chronic phase: The disease is stable. Most people have few symptoms.
• Accelerated-like features: In PV, ET, and PMF, the term “accelerated phase” is being replaced with “high-risk features,” which may include rising blast counts or specific genetic findings.
• Blast phase: Defined by 20 percent or more blasts (immature cells) in the blood or bone marrow. The blast phase behaves like acute leukemia.

In CML, only the chronic phase and blast phase are recognized in current classification systems.

What genetic changes are seen in myeloproliferative neoplasms?

Most myeloproliferative neoplasms are driven by somatic mutations, which are genetic changes that occur during life and are not inherited. These mutations affect how blood cells grow and divide.

Different types of MPNs are associated with characteristic mutations:

• CML: BCR::ABL1 fusion gene.
• PV, ET, PMF: Mutations in JAK2, CALR, or MPL.
• JMML: Mutations in genes that activate the RAS pathway.

Key driver mutations

A driver mutation is a genetic change that directly contributes to the development of the cancer. It “drives” abnormal cell growth by activating pathways that cause cells to multiply when they should not. Identifying driver mutations helps pathologists determine the type of MPN and guides treatment decisions.

Important driver mutations include:

• JAK2 p.V617F: Found in over 95 percent of PV cases and in about half of ET and PMF cases.
• JAK2 exon 12 mutations: Seen almost exclusively in people with JAK2-negative PV.
• MPL mutations: Found in 5–10 percent of ET and PMF and cause activation of the thrombopoietin receptor.
• CALR mutations: Found in 25–35 percent of ET and PMF. CALR type 1 and type 2 are the most common.
• BCR::ABL1 fusion: The defining mutation of CML, caused by a swap of genetic material between chromosomes 9 and 22 (the “Philadelphia chromosome”).

Many people with MPNs also have additional mutations in genes such as TET2, ASXL1, DNMT3A, EZH2, IDH1, IDH2, SRSF2, and U2AF1. These “secondary mutations” become more common as the disease progresses and may affect prognosis.

Are myeloproliferative neoplasms inherited?

Most MPNs are not inherited. However, some inherited genetic factors can slightly increase the risk of developing an MPN later in life. These include the JAK2 46/1 haplotype and rare variants found in certain families. Even when inherited factors are present, the disease still develops only after somatic (acquired) mutations occur.

Why is a myeloproliferative neoplasm important?

Myeloproliferative neoplasms can be slow-growing, and many people live for years with few symptoms. However, these conditions increase the risk of complications such as blood clots, bleeding, fatigue, or spleen enlargement. Some types may progress to more advanced phases or transform into acute leukemia.

Recognizing a myeloproliferative neoplasm allows doctors to choose appropriate monitoring, determine whether treatment is needed, and watch for signs of progression. Genetic testing provides critical information about the type of MPN and how it may behave over time.

Questions to ask your doctor

• What type of myeloproliferative neoplasm do I have?
• What is causing my blood cell counts to be high?
• Did my testing show a JAK2, CALR, MPL, or BCR::ABL1 mutation?
• Do I have any additional mutations that affect my risk or prognosis?
• What phase of the disease am I in?
• Do I need treatment now?
• How often should I have follow-up blood tests or bone marrow biopsies?