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We're learning more every day about how a mutation in an enzyme called JAK2 causes myeloproliferative disorders. Our new understanding of MPDs may lead to new treatments and a cure. What we've learned about MPDs Myeloproliferative disorders are rare diseases, and have often seemed mysterious to doctors and patients alike. These diseases were first described as “myeloproliferative disorders” in the 1950s, and although doctors could give a diagnosis and offer treatment, no one really knew the mechanisms behind these illnesses. This changed in a dramatic way in the spring of 2005, with the discovery of an acquired mutation in an enzyme called JAK2. Finding the JAK2 mutation is allowing researchers to take a major step forward in understanding MPDs. What is JAK2 and what does it do in our bodies? The story of JAK2 and MPDs begins inside our bone marrow. The long bones in our body contain a spongy tissue called bone marrow. Inside the bone marrow are special “progenitor” cells or stem cells, which can grow into any of the three types of blood cells in our bodies: red blood cells, platelets, and white blood cells. If we looked inside the stem cells, we would find different types of molecules that form a communications pathway for messages traveling inside the cell. One of these molecules is an enzyme called JAK2. When our bodies want to make more red blood cells, for instance, we send a hormone called erythropoietin (or EPO) out into our bloodstream. The EPO hormone travels through the bloodstream and eventually reaches the bone marrow, where it finds the stem cells. The hormone then locks onto a receptor site on the surface of the stem cell, which then in turn locks onto the JAK2 molecule inside the cell. This changes the structure of the JAK2 molecule, so that the JAK2 can transmit the message forward to other proteins on the communications pathway. The message tells the cell nucleus to grow and produce more red blood cells. Many patients with MPDs develop a mutation in the JAK2 enzyme. The mutation changes the way the JAK2 operates. The JAK2 doesn't simply transmit a signal in response to the EPO hormone, but instead acts on its own, amplifying the signal from the receptor. The excessively strong signal causes the body to produce too many blood cells. How does the discovery of JAK change our understanding of MPDs? We now know that many patients carry the JAK2 mutation, while many do not. (About 50% of ET patients and about 97% of PV patients test positive for the JAK2 mutation). Professor Tony Green of Cambridge University amongst others has proposed that we may want to reclassify the way we look at MPDs. In the past, we saw the MPDs as three diseases, albeit with some overlaps – ET, PV and MF. The news on JAK2 may challenge this paradigm and completely alter the way we classify MPDs. Based on the new information, we might think of classifying the MPDs into two diseases: a JAK2 mutation positive and a JAK2 mutation negative disease. There is some strong evidence pointing to this view. For instance, patients who carry the JAK2 mutation share many disease attributes. Some of these patients produce more red blood cells, and some produce more platelets, but this may in fact be due to the patient's particular genetic background or sex. Men, for example, produce more red blood cells. Perhaps we should look at JAK2 mutation-positive patients as having a single JAK2 positive MPD, rather than classifying them as ET or PV. Each group of patients goes through a chronic phase, which can last for a long time. Some patients worsen and develop myelofibrosis (either a JAK2 positive or JAK2 negative version) – we can think of this as an “accelerated” phase of the disease. A very few patients may move into a “leukemic” phase – in other words they develop leukemia. The discovery of JAK2 is changing the way we think about these illnesses. What we've thought of for many years as three diseases – ET, PV, and MF - may instead be two diseases: JAK2 mutation positive and JAK2 mutation negative MPDs. How can I be tested for the mutation? The JAK2 test is very simple, and it only requires a blood draw with a very small amount of blood. Results are available in one to two weeks. Results of the test will help your haematologist diagnose your disorder and potentially help him or her to optimise your treatment. How many people have the mutation? About half of ET and MF patients test positive for JAK2. Almost all PV patients carry the JAK2 mutation. What are targeted therapies? Targeted therapies are new kinds of drugs on the forefront of medicine. With advances in our understanding of genetic mutations, researchers are developing drugs that pinpoint weaknesses in a diseased cell's biology. There are new drugs called “small molecule drugs” or “signal transduction inhibitors” that can attach themselves to the problem proteins in our bodies, those that cause uncontrolled growth in the cells. These drugs stabilize the molecules and prevent them from sending growth signals. Drug trials are now underway in the E.U. and the U.S. to find safe and effective small molecule drugs to treat patients who carry the JAK2 mutation. Although new therapies could be many years off, with the discovery of JAK2 we now have the tools we need to develop medications that could one day cure MPDs. What if I test negative?We are learning that patients who do not carry the JAK2 mutation have a different kind of MPD than those who do. It isn't yet clear whether JAK2 negative patients carry other, different mutations that cause the disease. It can be a bit disconcerting to learn that you do not have the mutation, and would possibly not be able to receive the new medications if they become available, although it's not certain yet whether such drugs would be effective on all MPD patients. The good news for JAK2 negative patients is that the same techniques used to discover the JAK2 mutation are now being used to reveal other defects along the stem cell communications pathway. To see a lecture given by Prof Green re: JAK2 mutations and MPD go to European Hematology Association and click on plenary session 1. Further articles of interest: If you would like to learn more about other mutations that have recently been discovered, please go to the section: Research - New Mutations. You can read more about clinical trials in the United States on these websites:
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