The Story of MPL
A red mouse leads scientists down a twisting trail of discovery – to the cause of some blood cancers.
The story of the MPL gene and its association with certain types of blood cancers began with a single mouse. It was the afternoon of July 13, 1983, the day before the Bastille Day holiday in France. Martine Charon and Paule Varlet, two lab technicians at the Curie Institute in Orsay, were eager to leave work.
But their supervisor, virologist Francoise Wendling, insisted that the pair stay a little longer. Over the last few years, the team had been studying the effects of a virus on newborn mice and monitoring the animals’ health. Wendling wanted the technicians to check on the infected mice before departing.
Charon and Varlet reluctantly obeyed – and returned with surprising news. Usually, the virus triggered leukemia and anemia in one strain of mice, leading the animals to develop pale noses, ears, and feet. But the technicians had spotted an odd exception. “They came back in the lab and said, ‘There is a red mouse,’” Wendling said.
The mouse’s extremities had turned rosy due to an unusually high number of red blood cells. Upon further analysis, the scientists discovered that levels of platelets – small blood cells involved in clotting – and white blood cells called granulocytes in the animal also had skyrocketed. Massive numbers of these cells had invaded the spleen and liver, making the organs balloon to abnormal sizes. And when the researchers injected diluted blood plasma from that mouse into adult mice, the newly-infected animals developed similar symptoms.
Intrigued, Wendling and her colleagues isolated the virus from the first mouse and studied its genetic material. The virus no longer looked the same as the strain the researchers had originally injected. Instead, it appeared to have swiped a gene from the infected mouse and incorporated the blueprint into its own genome. In the process, part of the gene had been lopped off. When the virus replicated inside the mouse, the mutant gene had likely driven the strange disease.
The researchers named the new virus “myeloproliferative leukemia virus,” abbreviated MPLV. The normal, complete version of the mouse gene acquired by the virus was thus called MPL.
Scientists soon identified the MPL gene in humans as well. And they discovered that, unsurprisingly, MPL encodes a protein involved in blood cell production.
It turned out that the MPL protein is a type of molecule called a receptor. It spans the membranes of certain blood cells in the bone marrow, including stem cells and giant cells called megakaryocytes. The part of the receptor protruding from the cell binds to a specific blood hormone. When that hormone locks on, MPL sends a signal to the cell. Depending on the type of cell and environment in the bone marrow, the signal can help drive production or division of certain types of blood cells.
Studies began to emerge suggesting that MPL mutations could cause blood diseases in humans, similar to the way the mutant MPL gene had triggered the disorder in the mouse. In 2004, scientists reported a case of eight Japanese family members who produced too many platelets. All of the patients carried an MPL gene mutation, while eight relatives without the disease did not. The same year, researchers described a slightly altered MPL sequence found in about 7 percent of African-Americans, which also appeared to cause abnormally high platelet counts.
But could MPL mutations also cause cancer? Blood cancers called myeloproliferative neoplasms occur when a single stem cell in the bone marrow spontaneously acquires a new mutation. That stem cell then multiplies uncontrollably, leading to overproduction of blood cells. The first important clues to the genetic basis of these cancers arose in 2005 but not in MPL, rather in another gene named JAK2.
The protein encoded by JAK2 partners with MPL and other blood hormone receptors. When the receptors bind their respective hormones, they activate the JAK2 protein, which in turn signals other molecules in the cell to produce more blood cells. The mutated JAK2 protein, however, is hypersensitive: it sends
blood production signals even when the hormones are scarce or absent.
One of the teams that reported the JAK2 mutation was based at Brigham and Women’s Hospital in Boston. The researchers there decided to confront a new conundrum next: What drives these blood cancers in patients who do not have a JAK2 mutation? Yana Pikman, a medical student who had just joined the lab, set out to investigate. She and her colleagues sequenced blood cell DNA from 45 patients with normal JAK2 genes who had primary myelofibrosis, a type of blood cancer. Suspecting the answer might lie in receptors that partnered with JAK2, the researchers included MPL in their search.
Sure enough, Pikman’s team discovered an MPL mutation – an error in the 515th amino acid of the protein – in four patients. When the researchers introduced that same MPL mutation into mice, the animals developed a disease similar to primary myelofibrosis. The mice had high platelet and white blood cell counts, scarred bone marrow, and abnormally large spleens and livers. The mutation likely made the MPL receptor overactive, sending signals to produce more blood cells even when none were needed.
Over the next few years, researchers found MPL mutations in patients with other blood cancers, including essential thrombocythemia, acute megakaryoblastic leukemia (AMKL), and chronic myelomonocytic leukemia (CMML). Most patients carry the same error seen in Pikman’s study, although other mutations have been occasionally spotted as well. Scientists don’t yet know whether different types of MPL mutations signify different prognoses. Patients with MPL and JAK2 mutations have similar survival rates, but MPL patients tend to be diagnosed at older ages – perhaps because the disease takes longer to develop after the mutation occurs.
In 2011, the US Food and Drug Administration (FDA) approved a drug called ruxolitinib (trade name Jakafi) for treatment of myelofibrosis. The drug suppresses JAK2’s activity, and it has a similar effect on patients with JAK2 and MPL mutations. The treatment is imperfect: while ruxolitinib offers relief from symptoms, such as an enlarged spleen, it may not aid long-term remission.
But drugs targeting MPL also could help treat blood cancers. In a 2014 study, experimental hematologist Ian Hitchcock and his colleagues at the University of York in the U.K. tested the effects of reducing MPL levels. The team bred mice with the JAK2 mutation that produced half the normal amount of MPL. Instead of developing cancer, the mice appeared close to normal. In other words, subduing MPL counteracted some of the ill effects of the JAK2 mutation.
A drug that boosts MPL activity, called eltrombopag, already exists to treat patients with low platelet counts. So Hitchcock is optimistic that a drug that does the opposite – dials down MPL activity – can be developed as well. His team is working with other UK groups to investigate such a treatment.
Wendling, the co-discoverer of the virus that brought the MPL gene to light, is now retired and living in Paris. She tells young scientists not to ignore anomalies like the red mouse. “If there is something strange,” she says, “just jump on that.” Whether her team’s serendipitous finding will eventually lead to better treatments for blood cancer patients remains to be seen, but it certainly has helped scientists pinpoint some of the genetic missteps behind these diseases.