MPN Stem Cells Suffer From ‘Corrupting Influence’
Interferon has been shown to be very effective in some patients with MPNs, often alleviating their fatigue, enlarged spleen, and other symptoms. Some patients show important additional benefits, such as molecular response, even long-term remission and the delay of disease progression. For others with ET, PV or MF, interferon has no measurable effect. As part of the MPNRF Interferon Initiative, Joe Scandura, MD, PhD, wanted to understand more about why this is the case.
A hematopoietic stem cell biologist, the question led Dr. Scandura and his research team at Weill Cornell Medicine in New York to the question of cell fitness. Why and how does an MPN mutated stem cell win when in competition with normal cells?
MPNs originate in a stem cell. In fact, just a single cell can give rise to ET, PV or MF, as the mutated cell acquires attributes that allow it to outcompete normal cells, says Dr. Scandura. His question was how does this competition exist?
“It almost necessarily has to happen in the niche,” he explains, a unique microenvironment that provides the signals to a stem cell to allow it to exist, to do what a stem cell does. “A niche isn’t a static thing. It can change . . . to make stem cells basically hibernate, which is what normal stem cells spend most of their life doing.”
Their project involved using a niche created outside of the body. They asked the question: Does interferon target the MPN stem cells in humans, and if so, how well?
“What we set out to do is take a directly observable biological effect that I think most people would agree is the underlying biology of these diseases . . . be able to measure that in any person at any time. And then turn that into something that can be useful clinically to help identify treatments that are working in that patient.”
On any given day, a number of cells in our body are acquiring mutations. “Most of the time, they occur in a cell that doesn’t really much matter,” says Dr. Scandura. “But every now and then, there’s a mutation that occurs in the wrong gene (in a single stem cell).”
For that one founder mutation to become an MPN, “you need time and you need a fitness advantage,” according to Dr. Scandura. “To me, the whole game is why do those stem cells do better than our normal stem cells? Because if you can answer that question . . . and you can prevent that mutated stem cell from taking over, you can prevent the disease. And if you already have the disease? Well, those stem cells, if they can become less comfortable, can become less fit. Then the normal cells might be able to outcompete them.”
It comes down to this, according to Scandura et al. “We need to be understanding and targeting the stem cells, and stem cells don’t exist in a vacuum. They exist in a niche. That niche talks to the stem cell and the stem cell talks to the niche. And the mutant stem cells may be speaking in a language that’s slightly different than normal stem cells and telling the niche to do things that it doesn’t ordinarily do or shouldn’t be doing. So it’s kind of like a corrupting influence.”
Specifically, the research team looked across 12 different hematopoietic lineages to try to understand how these mutations propagated through hematopoiesis (the formation of blood) in people with different disease phenotypes. “What we realized early on is that there are patterns,” says Dr. Scandura. “And first we were associating this with diseases. We would see one kind of pattern in PV; we would see one kind of pattern in myelofibrosis. But then we started finding people who weren’t fitting with where they should be.”
When they started finding the exceptions to the patterns (i.e., ET that acted like PV or PV that acted like MF) they started looking a little bit more into who these patients are.
“These were our patients. I did bone marrows on people with PV because, for instance, they had symptoms associated with fibrosis. But then the results were marrow that still showed PV. Then a year later, we saw they have fibrosis. We realized that we actually were predicting things that were happening down the line a year, two years, three years later, and explaining things that we didn’t initially have an explanation for.” In essence, their biological experiment turned into an informal clinical experiment.
In their studies, they take the individual cells that are floating around in the blood and separate them. They then analyze how many mutant cells are within each of those populations and turn that back into one composite measure they call MPN fitness. “When we talk about fitness, it’s really that composite of how much can that mutated stem cell contribute to mutated blood cell production.”
Today, while there are MPN scoring systems used as prognostic indicators, and a limited number of predictive biomarkers, these look at clinical or molecular features to gage if a patient is likely to respond to a particular therapy.
“What we need is a monitoring biomarker, says Dr. Scandura, “something that changes, that predicts an outcome. If you have a measure that tells you that this drug is doing something that’s moving in the right direction and you can back that up with data . . . then we can use these for clinical decision making. Then all of a sudden we’re attaching an immediately realizable measure to a predicted outcome and a treatment effect. And so that’s really what we we’re trying to accomplish.”