Targeting JAK2 in Myeloproliferative Neoplasms - Episode 3
A discussion of the role of the JAK2 mutation and other factors in the development of MPNs.
Srdan Verstovsek, MD: Let’s go to the role of the JAK2 mutation itself. I think it’s fair to say that it’s a major player in the disease existence and disease progression perhaps. But there are other factors. The driver mutations, calreticulin and MPL mutations are there in ET [essential thrombocythemia] and PV [polycythemia vera]. They’re typically exclusive of each other, and other nondriver mutations that we just talked about that are being tested for. You test for what, 104 different mutations? I test for 82. They may have a role in the biology of the disease, prognosis, and the response to therapy. What is this all about? I still hear about JAK2 is the cause. It doesn’t appear that it’s the cause; I have read many papers that other folks may walk around with a JAK2 mutation without disease, and may never have a disease. I think that requires clarification here. It’s not a JAK2-driven disease.
Andrew Kuykendall, MD: Yes, it’s interesting. As we’ve learned more about clonal hematopoiesis and the fact that these blood mutations occur in healthy patients without evidence of disease, we’re starting to rethink a lot of the strong associations we’ve made. I think you’re referencing a study coming out of the Danish population that shows that healthy people with no evidence of an MPN [myeloproliferative neoplasm], you’ll see a JAK2 mutation in over 3% of the population. You’re typically talking about older folks. But even when we look at clonal hematopoiesis, JAK2 is either the fourth or the fifth most frequent mutation seen in patients with clonal hematopoiesis, which shows that it’s probably not uncommon to have a JAK2 mutation. The question is, why do some people develop disease with a JAK2 mutation and why do others not develop disease with a JAK2 mutation?
I think it helps to go down and understand what’s the role of JAK2 in regular hematopoiesis, and JAK2 is a protein that interacts with the thrombopoietin receptor, and the EPO receptor, and the GCSF receptor. It’s involved the production of platelets, red blood cells, white blood cells. It’s part of the signal transduction that’s involved in hematopoiesis, but also inflammation. When we get a mutation in JAK2, it leads to hyperactivity of that process, and so it leads to both increased inflammation and increase in hematopoiesis. And that inflammation can over time lead to scar tissue.
The question is, what takes it from being just a mutation in the stem cell to being disease-related? I think that’s what we’re always trying to figure out. We keep saying that there may be a role for inflammation, this broad term inflammation. I think it’s hard to define what that means, but we do know that when we do association studies, people who have defects in their IL-6 [interleukin-6] receptor have an increased risk of having myeloproliferative diseases. People who have inflammatory bowel disease have an increased risk of myeloproliferative disease. People who smoke have it. These things of induced inflammation seem to maybe allow for that come out. I think one of the things that’s increasingly interesting is this story that sometimes these MPNs can exist in families.
I think we all have patients who have brothers, sisters, cousins, mothers, fathers, who have an MPN, and maybe it has a different driver mutation, and that’s super confusing to have a family member who also has an MPN. We tell them it’s not something that’s genetic, or it’s not heritable, but they still have it, and these are rare supposedly, but then they have different driver mutations. I think we’re increasingly realizing that there’s some sort of genetic susceptibility that plays in a role in this where certain families are more prone to these, even if the JAK2 or the driver mutation per se is not passed along.
Srdan Verstovsek, MD: Yes, this a fascinating discovery of a predisposition to developing an MPN of one or the other type in the larger pool of the family members. It’s not really inherited in a direct way at all. And there is no real reason to test anybody for it. It will show up with a high blood cell count on an annual physical, or with a big spleen. There’s no reason to worry about it in a general sense because you have a heart problem running in a family, high blood pressure running in a family. Well, this is another situation like that. It’s nothing you need to do something about, it’s just a fact.
But that combination of the proliferation and inflammation is the leading cause of the disease affecting the body of the patients, after all, in either a short [time], like myelofibrosis, or over decades, like in ET. But in either case, the underlying problem is the hyperactivity of the JAK-STAT pathway. It’snot 1 mutation. And it’s safe to say, and clarify one more time for everybody, that any of the JAK inhibitors that we have are not specific for a JAK2 mutation. They act on JAK family members, and they decrease the proliferation and the inflammation. I think that’s fair to say, inhibition of the JAK-STAT pathway in general. Would you agree with that?
Andrew Kuykendall, MD: Yes, I definitely agree, and I think it’s interesting, we talked about JAK2 interacting with all these receptors. But MPL and CALR do as well. MPL we know is the gene that encodes the thrombopoietin receptor, it leads it to constitutive activation, and that causes activation through the JAK-STAT pathway. Calreticulin kind of mimics that in an atypical way, but certainly activates the thrombopoietin receptor and ultimately ends up with activation of the JAK-STAT pathway. I often talk about how JAK inhibitors are disease-specific anti-inflammatory medications. They dampen that signaling, and by doing so that’s how they result in their therapeutic benefit.
Srdan Verstovsek, MD: The differences in why somebody with a JAK2 mutation may have ET versus PV or myelofibrosis, obviously, it’s not clear-cut, but you have given us some clues about other factors. They might be genetic factors, or epigenetic factors, or it might be some other factors that we don’t know about, the bone marrow environment, or milieu in the bone marrow that would make disease happen and be more aggressive.
The genetic complexity certainly has a part, that’s why we use it in the assessment of prognosis, in myelofibrosis in particular. I think that’s a very good summary of understanding the biology of the hyperactivity of the JAK-STAT pathway, contributing factors to disease existence, and even a progression through worsening factors, the same factors just worsen over time. Fibrosis worsens, the genetic complexity worsens, abnormality in chromosomes happen. That contributes to the aggressiveness of the disease, and in some patients to transformation to acute myeloid leukemia.
Transcript edited for clarity.