Researchers find rare mutation doesn’t always result in blood cancer

Researchers have found that a genetic mutation associated with a rare group of blood cancers does not always result in development of the disease. The work provides insight into the initial phases of the disease and may eventually lead to tailored monitoring techniques that improve patient outcomes.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers that cause the overproduction of red blood cells, some types of white blood cells, or platelets. Many cases of MPNs are driven by a particular mutation in the gene JAK2, called JAK2V617F.

“We were fortunate to have access to a population study that allowed us to look at the occurrence of this mutation in the general public,” says Jordan Snyder, assistant teaching professor of mathematics at North Carolina State University and corresponding author of the study. “That allowed us to see relationships between the mutation and instances of disease.” Snyder was formerly an assistant professor of mathematics at Roskilde University, Denmark, where the work was done.

The researchers looked at participant data from the Danish General Suburban Population Study, which contained blood samples and health questionnaires completed by residents of Zealand, Denmark. Of the nearly 20,000 participants, Snyder’s group identified 67 people with the JAK2V617F mutation.

“Specifically, we were able to get data on the participants’ variant allele fraction, or VAF, over a 10-year period from a sample of the general public, not just patients,” Snyder says.

“Every cell that has DNA has two copies of JAK2, but not every copy has the same mutation status,” Snyder continues. “VAF represents the number of mutated copies of the gene versus normal copies. Most of the work around this mutation is looking at the VAF of patients with cancer. But to figure out how the disease progresses from a healthy state, we need to look at VAF before cancer develops.”

The research team created a stochastic mathematical model to describe how the mutation might proliferate in blood stem cells, where it is believed to originate. According to the model, in 70% of cases the mutated cells were likely to outcompete their normal counterparts; in 18% of cases mutants had a competitive disadvantage compared to normal cells; and 12% showed neither an advantage nor a disadvantage.

Thirty-seven of the 67 people in the study with the JAK2V617F mutation were later diagnosed with an MPN blood cancer, fewer than might be expected based on previous research.

“While the exact mechanism of action from this mutation is not completely understood, the previous assumption was that the mutation would always eventually out-compete healthy copies, leading to cancer,” Snyder says. “But these data point to the idea that there is more to it. It’s not just the presence of the mutated gene – something is happening to help that mutated copy out-compete the normal ones.

“Next steps in this work will be looking at some of those potential other factors – such as chronic inflammation.”

The research appears in Proceedings of the National Academy of Sciences and was supported in part by the Lundbeck Foundation Fellowship under grant R335-2019-2300. Johnny Ottesen of Roskilde University and Thomas Stiehl of Roskilde University and RWTH Aachen University are co-senior authors. Other Roskilde University contributors include Morten Andersen and Johanne Gudmand-Høyer. Morten Kranker Larsen, Vibe Skov, Lasse Kjær, Christina Schjellerup Eickhardt-Dalbøge, Trine A. Knudsen, Christina Ellervik, and Hans C. Hasselbalch of Zealand University Hospital made up the clinical research team that designed the study and collected the data.

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Note to editors: An abstract follows.

“Mathematical modeling of JAK2V617F clonal expansion in a general population cohort”

DOI: 10.1073/pnas.2507773123

Authors: Jordan Snyder, North Carolina State University and Roskilde University, Denmark; Morten Andersen, Johanne Gudmand-Høyer, Johnny T. Ottesen, and Thomas Stiehl, Roskilde University, Denmark; Morten Kranker Larsen, Vibe Skov, Lasse Kjær, Christina Schjellerup Eickhardt-Dalbøge, Trine A. Knudsen, Christina Ellervik, Hans C. Hasselbalch, Zealand University Hospital
Published: June 17, 2026 in Proceedings of the National Academy of Sciences

Abstract:
The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers characterized by overproduction of one or more types of blood cells, which can lead to thrombosis and other complications. MPNs develop slowly and
are driven by a relatively small set of mutations in the hematopoietic stem cells (HSCs). Their slow development (over the course of decades) affords a unique opportunity to study their onset, but until recently few data have been available from individuals not yet showing overt disease. Thanks to the ambitious Danish General Suburban Population Study conducted in suburban Zealand, Denmark, we have identified a (n = 67) cohort of individuals harboring the most common driver mutation in MPN (namely JAK2V617F) and have obtained follow-up measurements of their variant allele fraction (VAF) spanning over 10 y.We show that these data are consistent with a Moran model governing the competition between healthy and mutated HSCs, and estimate the selective advantage of the mutant clone for each individual. Notably, we find that for many individuals, the change in VAF over many years is statistically consistent with zero, or even negative, selective advantage. This is in contrast to prior studies that have focused on patients diagnosed with overt MPN disease, in whom the mutant cells are almost always found to outcompete the healthy cells. Our results have implications for our understanding of the very early phases of MPN disease, and may contribute to early detection and personalized prediction of disease progression.