What Is the JAK2 Gene, and What Does it Mean for MPN Patients?
Dr. Mascarenhas:
So the JAK2 gene is a gene that we all have and encodes for a protein called a JAK2 protein, which is important for signaling inside cells. And we need it in order to enable and support hematopoiesis, the process of producing white blood cells, red blood cells, and platelets. The problem is, is that people can develop mutations which are alterations in that gene, in the blood cell compartment of the body, that then lead this protein to be always on, to be always active. And it's an enzyme, so it contributes to a signaling pathway that is like a light switch that's on all the time, and inappropriately signaling and providing the cell with this cue to divide, and to live, and to secrete inflammatory markers. It essentially supercharges the cell in an inappropriate way. So, a JAK2 mutation is a mutation in a gene that we all have. But when altered, contributes to the biology, and what we call the “pathophysiology” of myelofibrosis.
What Is the Role of Genetics in an MPN Diagnosis?
Dr. Mascarenhas:
Well increasingly, it plays an important role in the diagnosis of these diseases. So, it is part of the diagnostic criteria for establishing a diagnosis of polycythemia vera, essential thrombocythemia, myelofibrosis. And can be used sometimes in certain settings to track response to therapies, and changes in that mutation may signify a positive response to therapy.
It's important to realize that although the three most common driver mutations of the disease; JAK2 V617F, MPL 515L/K, and the calreticulin mutations are present in 90% of patients with myelofibrosis, for example. There are 10% that are triple-negative. They don't have one of these discernible mutations. So it's not uncommon that a physician, a hematologist, would send something called “next-generation sequencing,” which is when you look at a broader array or panel of genes that could be mutated. And that can provide both some diagnostic help, but also prognostic help.
So these mutations, whether they're driver mutations or non-driver mutations, can have – not always – but can have prognostic significance. They can help us refine that risk stratification, that prognostication, that helps us decide what is the best treatment course for a given individual.
What Is Molecular Profiling? How Can it Impact Treatment?
Dr. Mascarenhas:
So molecular profiling is really a vague and general term that just means looking at mutations in genes. Usually, that's done through next-generation sequencing. It's a platform in which your blood – or your bone marrow blood; so blood from the bone marrow, blood from your peripheral blood, can be sent to a lab. Sometimes it's done in the institution, sometimes it's sent out to a third-party vendor. And the company and the laboratory personnel will analyze those genes to look for the presence of mutations across – sometimes it's a panel of 10 genes, 20 genes. Sometimes it can be 400 genes. And that information is distilled into a report that tells the physician what mutations may be present, and sometimes to what degree, like what percentage of the cells express that mutation. And that can all be used these days; again, to help diagnose a patient and support the diagnosis, but might also be incorporated in prognostication.
It is not quite at the point, I would say, in myeloproliferative neoplasms and myelofibrosis specifically, it's not at the point where those mutations will necessarily help dictate a very specific treatment. So meaning you may have a mutation in a certain gene, but that may not help us pull out a very specific mutation-directed therapy. There are some cases; so for example, the Myeloproliferative Research Consortium, the MPN-RC, has a trial ongoing called the 119 study, which enrolls patients who have an IDH2 mutation. So, if you have this mutation in the right clinical context, you could be eligible for a combination of a JAK inhibitor like ruxolitinib (Jakafi), plus an IDH2 inhibitor like enasidenib (Idhifa). So, there are these examples where there are some molecularly defined therapeutic approaches. But in the commercial or standard of care approach of treating patients with myelofibrosis, we don't really use those mutations to specifically guide choice of treatment. Not yet.
The reality is, is that if you go to a center where MPNs are done exclusively and with a focus, there's obviously a lot more knowledge base surrounding the disease and the approach to the disease than in the community. Where the docs in the community, to their credit, have to see a whole variety of different types of diseases. Which personally, I think, is really hard to do, and I definitely couldn't do it. So it's a privilege to be able to do just one thing. And with that, enables us to have a little bit more insight and expertise in personalizing that approach to any given individual that may not be completely there in a community setting.
