Tag Archive for: primary myelofibrosis

What Is a JAK2 Mutation?

Editor’s Note: This resource, What is a JAK2 Mutation?, was originally published by MyHealthTeam.


One of the most commonly mutated proteins found in myeloproliferative neoplasms (MPNs) is the protein Janus kinase 2 (JAK2). This important discovery has changed how doctors diagnose and treat people with MPNs. We will be discussing both the JAK protein and the JAK gene.

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:

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 JAK2 mutations have been found in other parts of the JAK2 gene, primarily in PV 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.

What Causes JAK2 Mutations?

There are two main types of JAK2 mutations 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, changing the shape of the protein. When this mutation is present, JAK2 signaling is turned on and cannot be turned off, leading to uncontrolled cell growth. In the case of MPNs, this causes an overproduction of blood cells, leading to blood cancers.

Multiple Mutations

Many different 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 these occur in people with PV.

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 is when entire pieces of the protein are lost. Insertions occur 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 MPNs?

MPNs are caused by a mutation in a single stem cell found in the bone marrow. These mutations cause the cell to rapidly divide, creating too many of one cell type. JAK2 gene mutations are involved in many cases of MPNs. In addition to JAK2 genesmutations found in CALR and MPL genes are also 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. The doctor will begin with a physical examination and health history. They may also order a complete blood count (CBC) with a differential, which assesses the number of red blood cells, platelets, and white blood cells.

Because most MPNs are associated with a specific genetic mutation, a pathologist may use blood samples to test for these. Two tests used to identify genetic abnormalities are quantitative polymerase chain reaction (qPCR) and fluorescent in situ hybridization (FISH). Typically, only one of the two tests is required for diagnosis. It is also an option to perform DNA sequencing to identify the driving mutation in an MPN case.

Quantitative Polymerase Chain Reaction

Quantitative polymerase chain reaction (qPCR) is the most commonly used method for diagnosing JAK2 mutations. qPCR 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.

Fluorescent In Situ Hybridization

This test determines whether someone has chromosomal abnormalities contributing to a cancerous phenotype. For example, one type of MPN, chronic myeloid leukemia (CML), is characterized by the presence of a Philadelphia chromosome (named for where it was discovered). A Philadelphia chromosome forms when two pieces of broken chromosomes stick together. This is also called the BCR-ABL1 gene, because one broken piece contains the BCR gene, and the other contains the ABL1 gene.

Most people with MPNs who are Philadelphia chromosome-negative (Ph-) have the V617F mutation in JAK2. This important discovery revealed the driving mutation behind Ph- MPNs. Before the discovery of JAK2 mutation, the cause of these defects was unknown. This also led to the development of specific JAK2 inhibitors for treatment of myeloproliferative disorders.

In 2016, the World Health Organization (WHO) revised its document “WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.” This revision included new criteria for diagnosing MPNs by the three main driver mutations in JAK2, CALR, and MPL genes. PV is characterized by the presence of a JAK2 mutation. ET and MF 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 inhibitors targeting the protein. There are currently two JAK2 inhibitors approved by the U.S. Food and Drug Administration (FDA) for the treatment of MPNs:

Jakafi

Jakafi (ruxolitinib) is approved for treatment of MF hydroxyurea-resistant PV. It is also being investigated for use in people with hydroxyurea-resistant ET. Additionally, some trials are investigating the effects of Jakafi in combination with the antimetabolite chemotherapies Vidaza (azacitidine) and Dacogen (decitabine). Antimetabolites are a special type of cancer drug that interfere with DNA by acting as a substitute for the normal building blocks of DNA.

Inrebic

Approved in 2019, Inrebic (fedratinib) is the newest MPN drug in almost a decade. It’s used to treat three forms: high-risk MF, post-polycythemia vera MF, and post-essential thrombocythemia MF with splenomegaly (enlarged spleen).

Other JAK2 inhibitors are currently in phase 3 clinical trials, including Pacritinib for the treatment of MF and severe thrombocytopenia, and Momelotinib for the treatment of MF. These promising new drugs are in final phases of testing.

Overall, the discovery of JAK2 mutations in MPNs has helped advance drug research, development, and MPN treatment. It has also helped 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.

Finding Support With an MPN

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 has tested positive for a JAK mutation? Did your doctor explain what the results of the test mean for your condition? Share your experiences on myMPNteam.

Primary vs. Secondary Myelofibrosis: What’s the Difference?

Primary vs. Secondary Myelofibrosis: What’s the Difference? from Patient Empowerment Network on Vimeo.

Are primary and secondary myelofibrosis different? Dr. Joseph Scandura, a specialist in myeloproliferative neoplasms (MPNs), explains the diagnoses and shares insight into each type.

Dr. Joseph Scandura is Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura, here.

Related Programs

COVID-19 Vaccination: What Do Myelofibrosis Patients Need to Know?

Expert Perspective: Promising Myelofibrosis Treatment Research

What’s YOUR Role in Making Myelofibrosis Treatment Decisions?


Transcript

Katherine Banwell:

Dr. Scandura, would you start by introducing yourself?  

Dr. Scandura:

Sure. My name’s Joe ScanduraI’m an assistant professor at Weill Cornell Medicine in New York City. I’m a physician scientist. My laboratory studies blood formation, normal and malignant, and clinically I treat people with  myeloid neoplasms, particularly, and myeloproliferative neoplasms.  

Katherine Banwell:

Would you define myelofibrosis for us, and also provide an explanation of primary versus secondary myelofibrosis? 

Dr. Scandura:

Sure. Myelofibrosis is in the class of diseases called myeloproliferative neoplasms. And, really, its sort of marker feature is scarring in the bone marrow.  

Clinically, this comes along most commonly and fairly universally with anemia, and there can be abnormalities of both the white blood cell count and the platelet count, sometimes, often in the beginning, being too high. And then they can also become too low. 

It tends to be a progressive disease, or on the face on which it progresses is different in different people and there are a variety of different features that can go along with risk. But every individual, of course, is individual.  

A primary myelofibrosis is what we refer to when the diagnosis is made and there’s no antecedent, there’s no precursor malignancy. And so, you come in and the diagnosis is myelofibrosis, and we can’t find anything that came before it.  

Secondary myelofibrosis is what we refer to when somebody has another blood disorder, usually essential thrombocythemia or polycythemia vera, and in a small subset of these patients, the disease can change, what we call evolve or progress into a fibrotic phenotype or associated with the marrow scarring, and a lot of the features of myelofibrosis. Although there are some subtle differences between primary and secondary, they’re more similar than different in terms of their clinical features and how we treat them. 

Persevering Through Clinical Trials

Andrew Schorr talks with patient advocate, Voncille “Peppe” Fryou about her journey with cancer and clinical trials. She begins by explaining that after 10 years without an accurate diagnosis, Peppe finally found out why she was tired all the time…Primary Myelofibrosis (PMF). To beat this disease, she has been enrolled in four different clinical trials, and is now currently participating in the PRM-151 trial. One thing she has learned from her experience is that patients need to be active participants in their studies. Watch the video below for Peppe’s full story and advice on clinical trials.

Persevering Through Clinical Trials from Patient Empowerment Network on Vimeo.

[accordion]
[toggle title=”Full Transcript Here” state=”closed”]

Andrew:    

Peppe, you’re from where in Louisiana?

Peppe:    

Lafayette, Louisiana, which is on the Gulf Coast.

Andrew:     

And you were diagnosed with primary myelofibrosis just like me right off the bat.

Peppe:

Um-hmm.

Andrew:     

How did it present itself?

Peppe:   

I was tired all the time. For years and years, I was tired. And we did all sorts of tests, and they would come back negative. The only thing they ever came back with was Epstein Barr virus, which they said I had chronic fatigue syndrome.

Andrew:  

So you went how many years before you got an accurate diagnosis?

Peppe:  

Let’s see, probably 10 years.

Andrew:

So it can happen. So you have this diagnosis, and you were very sick.

Peppe:

Yeah.

Andrew:

You eventually got over here to MD Anderson, Dr. Verstovsek. And you’ve been in a number of clinical trials.

Peppe:

Yes.

Andrew:

And you’ve had highs and lows with those. It’s not always been perfect at all.

Peppe:

Exactly. Sometimes, particularly me, I started off well, but didn’t end out very well. I sort of started off good, and then I just started going downhill. And so Dr. V says we’re going to try something else. We’re going to try something else. Are you for that? Yeah. We made a pact. He said as long as he’s being a doctor that I have to stay here and be his patient. So I stayed on his butt all the time. You got to keep me alive, doc. Get busy. And he did.

Andrew:

So you’re on one of these trials we mentioned, the PRM-151 trial.

Peppe:     

Yes.

Andrew:  

What does that involve?

Peppe:     

I get an IV. I go through my clinicals. I get an IV. And I go home. No side effects, nothing.

Andrew: 

Is this an infused medicine?

Peppe:  

Yes. Several years ago, I had a port put in because of some of the medications that would make my counts drop. I needed blood transfusions. And the vein thing got old real fast because it was years I needed the transfusions. So I had a port put in. The doctor did a botched job with that. I had another port put in. He did a terrible job with that. So I came to MD Anderson and said put me a port in. And now, I have an excellent port, and everything works fine. And it’s just hook me up, and –

Andrew:    

One last thing is so you’ve had quite an adventure with myelofibrosis. What’s your view of today and the future right now?

Peppe:     

Oh, we’ve come so far. I mean, like I said, this is my fourth study. Plus, I was on the medication Jakafi. It really wasn’t – he may disagree with me. It really wasn’t a good drug for me. And I put on 50 pounds. And I’m just too little for that. But I’ve gotten that weight off. But I think that it’s important that patients stay active in the studies. I’ll tell you why I agreed to team up with Dr. V. I had a friend years ago that had Hep C. And she got in on a study someplace in New Orleans, Tulane or some place. And she stayed on that study through hell and back. She fell asleep at her desk. But if she missed days of work, they were going to back off on her medication. And her best survival rate was taking it full force. So she did it. She did it. She’s still alive today. And so that’s my hope and my dream for all of us is that our experts are going to find what it is that we need to be cured or control it.

[/toggle]
[/accordion]