Myeloproliferative neoplasms (MPN) are a group of slow-growing blood cancers that are caused by an overproduction of various blood cell types. “Myelofibrosis is when your bone marrow is making too many fiber cells and preventing the bone marrow from making normal blood cells,” Dr. Adrienne Phillips, a hematologist/medical oncologist at Weill Cornell Medicine, tells SurvivorNet.
There are six main MPNs, and genetic testing has demonstrated a majority of Philadelphia-negative myeloproliferative neoplasms (MPN) be caused by the JAK-2 mutation.Read More
What is a Mutation?
Cancer can be caused by various mutations. A mutation is a change in DNA that can cause cells to grow abnormally and irregularly. MPNs typically occur due to non-hereditary (or acquired mutations). These can occur due to environmental factors or during normal cellular replication. There are several mutations observed in Myeloproliferative Neoplasms. Examples include the following:
- JAK2 V617F
- JAK2 Exon 12
All these mutations can contribute to cellular proliferation (cell growth and division) in patients with MPN. While the BCR-ABL1 mutation is connected to the diagnosis of chronic myeloid leukemia (CML), the JAK-2, CALR, and MPL mutations can commonly be found in patients with other forms of myeloproliferative neoplasms.
JAK-2 Positive Myeloproliferative Neoplasms
The JAK-2 protein works by signaling hematopoietic growth factors. Hematopoiesis is a scientific way of saying the development and formation of blood cells. So, JAK2 proteins can signal certain elements that are needed to create blood cells.
Normally, JAK-2 proteins can provide both an “on” and “off” signal to regulate the number of cells being created. In patients that are positive for the JAK2 V617F mutation and have a myeloproliferative neoplasm, the JAK-2 protein is always activated (turned ‘on’), resulting in an overproduction of cells. If you have a mutation on the JAK-2 protein, your healthcare team may say you are positive for a JAK2 myeloproliferative neoplasm or may simply say you are JAK-2 positive. Both phrases are used interchangeably in medicine.
JAK-2 V617F Positive Myeloproliferative Neoplasms
There are over 50 different JAK-2 mutations presently known, with the most common being JAK2 V617F. The JAK2 V617F mutation is found in the majority of patients with the following MPNs:
Because of this, National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing for the JAK2 V617F mutation in patients with suspected myeloproliferative neoplasms (MPN). Testing for the mutation can be done either by testing the patient’s blood or bone marrow.
JAK-2 Mutation in Myeloproliferative Neoplasms (MPNs)
- MPNs typically occur due to non-hereditary (or acquired mutations). These can occur due to environmental factors or during normal cellular replication.
- If you have a mutation on the JAK-2 protein, your healthcare team may say you are positive for a JAK2 myeloproliferative neoplasm or may simply say you are JAK-2 positive.
- Normally, JAK-2 proteins can provide both an “on” and “off” signal to regulate the number of cells being created. In patients that are positive for the JAK2 V617F mutation and have a myeloproliferative neoplasm, the JAK-2 protein is always activated (turned ‘on’), resulting in an overproduction of cells.
- Cytoreductive therapy, JAK inhibitors, phlebotomy, and low-dose aspirin are some of the treatment options available to manage MPN.
JAK-2 Myeloproliferative Neoplasms: How the Mutation Impacts Different MPNs
Polycythemia Vera (PV)
According to the MPN Research Foundation, nearly 95% of patients with PV have a JAK2 mutation. “Because the JAK-2 protein is always ‘on’”, Dr. Ghaith Abu-Zeinah, an instructor in Medicine at Weill Cornell Medical College and an Assistant Attending Physician at the New York-Presbyterian Hospital, says “ this leads to excess proliferation of blood cells”. . For patients with PV, this results in a higher number of red blood cells (RBC).
In addition to a higher number of overall red blood cells, patients are also normally observed to have an elevated amount of the following in their blood:
- Red Cell Mass
Although patients may have higher levels of the components listed above, at least one is needed in addition to an elevated overall RBC count to make a proper PV diagnosis.
Essential Thrombocythemia (ET)
The JAK-2 protein can signal the creation of a cell called a megakaryocyte. These cells mature into platelets. In patients with essential thrombocythemia, mutations such as the JAK2 V617F mutation, cause too many platelets to be produced. It is estimated that 60-65%of patients with ET have the JAK2 mutation.
Platelets are essential in the regulation of blood clotting throughout the body when available in normal amounts. Excess number of platelets, which is seen in ET, can increase the risk of unwanted clotting and other thrombotic/cardiovascular events (like stroke or heart attack).
Primary Myelofibrosis (PMF)
Megakaryocytes can also perform many functions throughout cellular development. One of the functions includes signaling and stimulating other cells to produce collagen. Collagen is a protein within the body that is used to provide structural support within the body. Whenever there is too much collagen, it can cause fibrosis (or scarring).
In patients with PMF, overproduction of collagen can lead to scar tissue to form and build up within the bone marrow itself. Overtime, the scarring increases and can replace the bone marrow. With less bone marrow within the bone, there are fewer healthy red blood cells that can form.
Treatments for Patients with JAK2 V617F Positive MPNs
After being diagnosed with an MPN, your healthcare team will assess your risk status. In patients with PV or ET, risk is calculated by looking at your age and prior medical history. If you have ET, having a JAK2 V617F mutation puts you at higher risk of disease progression. Risk for patients with PMF is determined based on past medical history and evaluating if a patient is currently symptomatic.
One of the main courses of treatment is cytoreductive therapy. Like the name suggests, cytoreductive therapy can be used in patients with the JAK2 V617F mutation to reduce the number of blood cells (“cyto”) in the body. Common medications used include hydroxyurea and interferon alfa, amongst others.
Cytoreductive therapy is generally reserved for higher risk PV and ET patients or in patients that are lower risk with symptoms or bleeding episodes. It can also be used in low-risk patients with PMF that are symptomatic.
Dr. Abu-Zeinah explains to SurvivorNet, “the treatment of myleofibrosis, is really down to a couple of FDA approved drugs “. There are targeted medications available that work to prevent signaling of the pathway that the JAK-2 protein works upon. This prevents the JAK2 V617F mutation from being able to signal overproduction of blood cells.
Examples of JAK inhibitors that are available to treat MPNs include:
It is important to point out that although these medications are beneficial for patients with the JAK-2 V617F mutation, they can also work in patients with certain MPNs that do not have the mutation. Treatment with medications that inhibit JAK pathway is typically reserved for patients with intermediate or high-risk forms of PMF. Ruxolitinib (Jakafi©) may also be used for PV in patients who have had inadequate response to other therapies, such as hydroxyurea.
Phlebotomy is a procedure used to reduce the number of red blood cells. Patients diagnosed with PV may use phlebotomy as a part of their treatment regimen.
To decrease the number of red blood cells that are produced due to mutations, such as the JAK2 V617F mutation, your provider will remove a small amount of blood with the goal of decreasing hematocrit levels (% of red blood cells). By decreasing hematocrit levels, the body will have less iron available for the bone marrow to use to create new red blood cells.
The length of time between each phlebotomy procedure is different for each patient. If your healthcare team believes phlebotomy is right for you, it may begin more frequently (ex: weekly) then decrease as symptoms become more manageable or controlled.
Low-dose aspirin (40 to 100 mg by mouth once or twice daily) should be given to all patients with PV unless there is a specific contraindication. This treatment is safe and effective for preventing thrombosis in PV and for relieving microvascular symptoms, such as shortness of breath. sleep problems. fatigue, and lack of energy.
Moving Forward – Questions to Ask Your Doctor
- Does my MPN carry the JAK2 mutation?
- Am I eligible for any treatments that target the JAK2 mutation?
- What does my JAK2 status mean for my prognosis?
- How do I know if my treatment is working?