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What Do Gene Mutations Mean in MPNs?

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Published on January 22, 2020

Myeloproliferative neoplasm  expert Dr. Catriona Jamieson, from UC San Diego Moores Cancer Center answers a question from the Patient Power community by explaining the different cancer genes that drive MPNs and their associated risk level. Dr. Jamieson also shares information on inhibitors and treatment options for various gene mutations. 

This is an MPN Research Foundation program produced by Patient Power. We thank Celgene for their financial support through grants to the MPN Research Foundation. These organizations have no editorial control, and the program is produced solely by Patient Power.

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Transcript | What Do Gene Mutations Mean in MPNs?

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:         

I think many of us have learned that not all MPN is alike and that there are cancer genes that drive your MPN or mine. Mine is JAK2V617F, because Dr. Jameson did the testing for that. It can change to what's your gene, what's your driver gene on your—so, here's a question we got from Jerry, who said, "Why is CALR type 1 considered low risk, despite high symptoms at the time?" So, CALR is another gene.

Dr. Jamieson:             

Right.

Andrew Schorr:         

So, he's saying is it considered low risk?

 

Dr. Jamieson:               

Yeah, I think it's the kind of risk that we're talking about. Usually when we ascribe risk to a gene mutation, like the JAK2 mutation, we're really talking about the risk of progression of scarring in the bone marrow. So, myelofibrosis. "Myelo" means bone marrow. "Fibrosis" means scarring. Can progress from grade 0, which is a little bit, all the way up to grade 3, which is a lot of reticulin. And then collagen fibrosis, which is stained with trichrome stain. So, it's really the risk of progressing with regard to myelofibrosis and then also transforming to acute leukemia. It doesn't really take into account so much the risk of clotting, stroke, heart attack, clotted into the hepatic vein or deep venous thrombosis. And so, for the calreticulin mutation, we think there's a slightly lower risk of myelofibrosis progression and a slightly lower risk of acute myeloid leukemia, but there's a slightly lower chance of responding to JAK2 inhibitors.

So, even though people with a JAK2 mutation maybe have a slightly higher risk of progressing, they're more likely to respond to a JAK2 inhibitor, because they've got more target. So, with the calreticulin mutation, you can still activate the JAK-STAT signaling, but it's not as robust as with the JAK 2V617F mutation. 

Andrew Schorr:

 So, is there a CALR medication?

Dr. Jamieson:             

There isn't. Whether—the thing with the CALR mutation is that you can—and there are two different types of mutations, but both can activate JAK-STAT's signaling, so they should be sensitive to JAK-STAT inhibitors. They just won't be as sensitive as somebody with a JAK2 mutation. So, the people with a JAK2 mutation tend to respond really nicely.

Andrew Schorr:         

And I should mention I've been on the JAK2 inhibitor for seven years and I'm going scuba diving after this conference. So, really there's a—you know, you want to have as full of life, and if there's a medication that can work and you get the right dosage, that's your discussion with your doctor.

Dr. Jamieson:             

Well, there is one more thing we're interested in for CALR mutated disease, and that's can we focus on this survival set of genes called Bcl-2 and Bcl-XL? And those look like very interesting targets. So, as you remember in the field of chronic lymphocytic leukemia…

Andrew Schorr:         

…I do. 

Dr. Jamieson:               

There was a drug that was made for that called Navitoclax. And venetoclax (Venclexta) is already used in CLL. Navitoclax stopped being used, because it targets both Bcl-2 and Bcl-XL. Well, it turns out that's exactly what you want in essential thrombocythemia. And it's actually what you want in certain people with myelofibrosis, who tend to have higher platelet counts. And that's more like what we see with the calreticulin mutation. So, that might be a very good opportunity for people with the CALR type-1 mutation who haven't responded to JAK2 inhibition. So, they may want to get on to Navitoclax at some point in the near future.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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