The Story of CSF3R
A research team finds a mutation behind a rare blood cancer.
White blood cells are the ambassadors of your immune system – ambassadors that can resort to deadly force if needed. The majority of these white blood cells are neutrophils, a kind of cell that’s made in the bone marrow and zooms off to protect you against bacterial and fungal infection. Like a firefighter or an EMT, they’re often the first cells that show up at the infection site.
Neutrophils are part of a group of cells known as granulocytes (they get this name from what they look like – grainy – when stained and examined under a microscope). They can swallow up infected cells, and also produce types of proteins called enzymes that can terminate an invading microorganism. And when people don’t have neutrophils, or don’t have enough, they’re prone to bacterial and other infections.
Mutations in the CSF3R gene can cause CNL
Researchers who looked at tissue samples from people with CNL patient – studying the sequence of genes and the way cells reacted to an assortment of cancer drugs – found that mutations in the CSF3R gene can cause CNL. One mutation that’s often seen in people with CNL results in the receptor protein being switched “on” without the need for its partner protein, GCSF, so that it can start the series of reactions that lead to too many neutrophils.
Mutations in the CSF3R gene may also play a role in other blood cancers such as atypical chronic myelgenous leukemia (aCML).
But too many neutrophils can point to a problem, too. In people with chronic neutrophilic leukemia (CNL), a rare blood cancer, neutrophils spill out of the bone marrow, crowd the blood, and pile up in the liver and the spleen. With so many white blood cells jockeying for position in the bloodstream, these people have trouble making red blood cells and platelets. So they often develop anemia, fatigue, and other problems that go along with having too few red blood cells. If the disease progresses, it can be fatal, with a median survival of two to three years.
For years no one knew exactly how CNL developed. At Stanford University Medical Center, hematologist Jason Gotlib spent more than a decade collecting tissue samples from people with CNL and another rare blood cancer, atypical chronic myeloid leukemia (aCML). In 2007, he began sending these samples to cancer researchers at Oregon Health & Science University in Portland.
The OHSU researchers studied cancer with a combination of genetic testing and checking how cancer cells responded to specific drugs. When they first got the samples from Gotlib, the group saw interesting patterns, but didn’t have the technology to look more closely. But by 2011, cancer researcher Jeffrey Tyner and his colleagues had developed a series of steps to study the genetic mutations in a person’s cancer cells, while also looking at how each of these mutations responds to drugs They began looking at the tissue samples Gotlib and other researchers sent to them, trying to find any mutations that might be behind these seldom-seen diseases.
One of the many genes they looked at was CSF3R. The CSF3R gene encodes a protein called granulocyte-colony stimulating factor (GCSF) receptor. This GCSF receptor is like a bridge that spans the cell membrane. On the outside, it binds with a partner protein, GCSF; once protein and receptor bind, the part of the receptor on the inside of the cell starts sending signals to the rest of the cell.
Within the bone marrow, there are lots of precursor cells – cells with wide-open futures, which haven’t yet become what they will become. These cells have the GCSF receptor, and when it’s turned on by binding with GCSF, it starts a chain reaction that produces more granulocytes, and in particular, more neutrophils. Binding between protein and receptor can also affect how mature neutrophils function; GCSF rallies neutrophils from their birthplace in the bone marrow into the blood, and can regulate a wider immune response by neutrophils, too.
A blood test can confirm a CSF3R mutation and diagnose CNL
Not all laboratories test for a CSF3R mutation. If your doctor thinks you may have CNL, your blood work may be sent to a research laboratory that can check for this mutation.
As the researchers looked at the genes from cancer cells of 27 CNL and aCML patients, they found that nearly 60 percent of these people had cancers that carried mutations in the CSF3R gene. (More recent work has suggests that as many as 80 percent of CNL patients have this mutation; it’s less common in patients with aCML.)
The most common mutations that they saw affect the part of the GCSF receptor protein outside the cell. Essentially, these mutations turned the receptor on permanently – the receptor no longer needs its partner protein to work. This transforms the cell into a neutrophil-making machine on autopilot, which explains the excess neutrophils found in CNL. For CNL – a cancer that doctors had only seen previously in about 200 people – finding this mutation in a genetic test can confirm that this is exactly the disease they’re looking at. But once Tyner and his colleagues published their results, they started hearing from more doctors, from all over the world. While the disease still is far from common, he says, CNL cases “may be a little bit more common than people thought.“
Knowing about mutations in this gene also may help in finding treatments. When the GCSF receptor is turned on, as it can be when its gene has a mutation, this receptor kicks off a signaling pathway that includes a protein called janus kinase 2 (JAK2).
A new clinical trial for people who have CNL or a CML – whether or not they have a CSF3R mutation – is enrolling participants
People with CNL or a CML are needed for a current clinical trial at seven research centers across the country. Participants, who don’t need to have a CSF3R mutation to be involved, will be given ruxolinitib, a cancer drug that targets a pathway connected to the work CSF3R does in the cell. In preliminary tests in a handful of people, ruxolinitib helped reduce the number of neutrophils and increase the number of platelets for CNL patients.
In the past, researchers had developed an inhibitor to the JAK2 protein known as ruxolinitib (marketed as Jakafi), currently used to treat bone marrow disorders; in Tyner’s lab, researchers found that ruxolinitib inhibited the growth of cells with CSF3R mutations that turned on this pathway. One person, whose cells responded particularly strongly to ruxolinitib, started taking ruxolinitib orally; their white cells and neutrophil levels dropped, and the level of platelets in their blood returned to normal.
Now, researchers have started to investigate this treatment for people with CNL and aCML that may have CSF3R mutations that activate this pathway. At OHSU’s Knight Cancer Center, along with six other sites across the country, participants will receive ruxolinitib whether or not they have the CSF3R mutation.
Researchers are also hoping to make the test for this mutation more widespread when diagnosing the disease. If a doctor suspects that someone has CNL, a blood test can confirm the presence of CSF3R mutations, but not all laboratories test for these mutations.
Learning more about what mutations a person has may help how the disease is treated, too. Tyner has heard of significant responses to ruxolitinib in people who have CSF3R mutations that switch on the receptor. “We’re seeing good improvement in quality of life,” he says, although he cautions that the response isn’t as strong as with treatments for other cancers, like imatinib (marketed as Gleevec) for chronic myelogenous leukemia (CML). There are often second mutations that occur in other genes along with the mutation in CSF3R. For CNL, Tyner says, “ultimately, we’ll need combination therapy.”