Involved in: blood cancers and disorders including polycythemia vera, primary myelofibrosis, thrombocythemia, and leukemia.
Testing requires: a blood draw. Bone marrow samples occasionally used.
Prognosis: patients with a JAK2 mutation have a lower survival rate and higher rate of blood clots compared to patients with a CALR mutation.
Treatment: ruxolitinib may improve quality of life in patients with a JAK2 mutation.
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At a 2004 scientific conference in Portugal, Robert Kralovics felt nervous. Kralovics, a geneticist at University Hospital Basel in Switzerland, and his colleagues had been searching for the genetic defects responsible for certain blood cancers. Earlier that year, the team had narrowed down the potential genes involved to about a dozen candidates, including one named JAK2.
But at the meeting, Kralovics got wind that other scientists might be working hard on the same problem. He feared that another team would report a mutation first and get credit for the discovery before his group could finish its experiments. While patients would benefit either way, Kralovics also had his career to consider: if he was “scooped,” years of his work would essentially be wasted, and his chances of securing future jobs and research funding would diminish.
“It unleashed hell in the lab,” he says. Back in Switzerland, Kralovics’s supervisor, Radek Skoda, put about half a dozen researchers to work on the project. For the next several months, Kralovics toiled until 2 a.m. nearly every night.
Just as Kralovics suspected, three other teams also had zeroed in on JAK2. In a suburb of Paris, hematologist William Vainchenker and his colleagues at the Institut Gustave Roussy investigated how the gene affected growth of cells from patients with polycythemia vera, a cancer in which red blood cells are overproduced. Across the English Channel, a University of Cambridge team sequenced parts of JAK2 in cells from 140 blood cancer patients. And an American group in Boston recruited patients online to provide blood samples, then searched those samples for errors in dozens of genes.
The four competitors published their results in rapid-fire succession in March and April of 2005. Each team had taken a different approach, but all identified the same mutation: a mistake in the 617th amino acid of JAK2. The researchers found the mutation in most patients with polycythemia vera as well as in many people with related blood cancers called essential thrombocythemia and primary myelofibrosis.
The discovery was “a really big deal” in the scientific community, recalls Ann Mullally, a hematologist-oncologist at Brigham and Women’s Hospital in Boston. “To have four groups using different methods in four different countries all coming to the same conclusion—that’s pretty overwhelming evidence that this is a real mutation.”
It made sense that a JAK2 mutation was behind the cancers. The protein encoded by JAK2 transmits signals involved in blood production. When certain hormones latch onto cells in the bone marrow, the JAK2 protein becomes activated and passes the message to other molecules inside the cell, which eventually trigger production of blood cells. Normally, the body makes blood cells only in response to those hormones. But when JAK2 is mutated, this carefully regulated system goes awry. A mutated JAK2 protein sends messages to increase blood production even when little or no hormone is present. The hyperactive signaling leads to overproduction of blood cells.
John Crispino, a blood cancer researcher at Northwestern University in Chicago, compares the situation to a restaurant. A waiter should send orders to the kitchen only when customers have sat down and requested food. But a mutated JAK2 protein behaves like a waiter gone berserk. Instead of waiting for customers’ orders, the waiter constantly tells the kitchen staff to churn out salads, entrees, and desserts even when the restaurant is empty.
The discovery of the JAK2 mutation spurred a wave of clinical improvements. Doctors could diagnose patients more accurately by testing blood samples for the mutation. A positive result indicates that the patient has blood cancer rather than another disorder that causes blood overproduction as a side effect. And drug companies rushed to develop cancer drugs that targeted JAK2.
The first such drug to hit the market was called ruxolitinib. A mere six years after the JAK2 mutation was reported, the Food and Drug Administration (FDA) approved ruxolitinib for treatment of myelofibrosis; in 2014, that approval was extended to some polycythemia vera patients. The drug relieves patients’ symptoms, such as enlarged spleens and inflammation, and improves their quality of life. However, ruxolitinib does not reduce the number of cancer cells. Patients are still waiting for a drug that will selectively kill off cells carrying the JAK2 mutation.
Scientists also have linked more mutations to these cancers. The University of Cambridge team found other types of JAK2 mutations that primarily cause overproduction of red blood cells. The Boston group and Kralovics’s team discovered new mutations in genes named MPL and CALR, respectively. Nearly all patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis carry a mutation in one of these three genes.
Patients’ prognoses can differ depending on their mutations. For instance, people with a JAK2 mutation have a lower survival rate and higher risk of blood clots than people with a CALR mutation. The variation might arise because JAK2 influences production of more types of blood cells, including white blood cells that help drive inflammation and blood clotting.
But many questions about JAK2 remain. Scientists still don’t understand how a single mutation can lead to three different cancers. Some researchers speculate that the amount of mutated JAK2 determines the disease. Patients who carry two copies of the mutated gene are more likely to develop polycythemia vera, while patients with essential thrombocythemia usually carry only one copy. The person’s underlying genetic makeup also might influence the type of cancer, although little evidence for this idea has emerged so far.
Kralovics is still kicking himself for not finding the JAK2 mutation sooner. In 2002, he had sequenced part of the gene in cancer patients—but missed the segment containing the error. If he had focused on a different part of the gene, he could have beaten his three competitors to the punch. But the race for results is not all about getting credit. “The competition is a nightmare for scientists, but it’s actually the best news for the patients,” he says. “It accelerates discovery.” The faster results emerge, the sooner diagnosis and treatment can improve. With JAK2, the leap from lab to clinic was impressively quick.