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In leukemia's most aggressive forms, the blood cell factories in our bone marrow falter. Instead of dividing and multiplying at their usual prolific pace, generating hundreds of billions of new cells daily, some precursor cells stall out at an immature stage.
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"They never finish. They never become what they should be. Because they are progenitor cells, they don't really have a function and just expand and collapse our bone marrow," said Raquel Espin Palazon, an associate professor of genetics, development and cell biology at Iowa State University.
New findings by a research team led by Espin Palazon identified two essential components—a pervasive protein and a crucial cellular signaling pathway—needed to make some types of blood cells, a discovery that could lead to a new treatment for leukemia.
Puzzling protein levels
The study, published in Cell Reports, sprang from the researchers' interest in progranulin, a protein found throughout most plants and animal bodies that plays a role in cell growth, tissue repair and inflammation. They wanted to know why progranulin is the most highly expressed gene in humans' macrophages, the large white blood cells that engulf and remove pathogens.
"Nobody had linked a function in macrophages with this protein. But there must be some reason it's so highly expressed," Espin Palazon said.
Directly studying progranulin in macrophages is difficult in mammals, which carry a single gene to produce the protein throughout their bodies. If scientists turn off that gene, the effects are too broad and interconnected to pinpoint what's happening in blood cells. But there are two types of progranulin in zebrafish, a common research subject for human health often studied by Espin Palazon and other Iowa State scientists.
In a study published in 2021, a team led by Espin Palazon showed that one of zebrafish's progranulin genes is expressed only in blood cells. That production is important because the protein is needed for progenitor cells called myeloids to develop into white blood cells such as macrophages and neutrophils, the researchers found.
To see if progranulin also drove myeloid maturation in humans, the researchers tried various methods of adding it to human leukemia cells. If the protein could make human myeloid cells differentiate into mature white blood cells, it could hold promise as a leukemia therapy. At first, it didn't work.
Second ingredient needed
To dig deeper, researchers returned to zebrafish altered to lack the type of progranulin found in blood cells. They analyzed what else went wrong when blood-cell progranulin was gone. One prominent defect was a pathway called JAK2/STAT3, which uses chemical signals to deliver information from outside a cell to the DNA in its nucleus. Both progranulin and JAK2/STAT3 were essential for myeloid progenitors to morph into macrophages.
JAK2/STAT3 is often hyperactivated in a variety of cancers, including leukemia. Adding progranulin to leukemia cells with an active JAK2/STAT3 pathway causes them to mature, allowing the cells to progress through their typically short-lived life cycle and eventually die, Espin Palazon said.
"It was super exciting to see the differentiation, that blockage in the human leukemia line being overcome," she said. "Adding progranulin, the missing component, could be a potential therapeutic target."
Figuring out both ingredients essential for myeloid differentiation is an example of why it can be beneficial to study living subjects instead of isolated cells, Espin Palazon said.
"Animal models are sometimes essential to drive discovery because they allow us to understand biology within the complexity of an intact organism—something that laboratory-generated systems cannot yet fully reproduce," she said.
A route for new research
A related finding included in the new study could also be potentially useful in human health research.
Some macrophages develop in embryos and become specialists, taking up a lifetime residence and self-renewing in a particular major organ such as the brain or heart. Espin Palazon's team found there are two types of embryonic macrophages, only one of which needs the JAK2/STAT3 pathway and progranulin to form. Embryonic macrophages that require both components are better at regenerating tissue to heal injuries, she said.
"This opens up possibilities for studying and dissecting the two different types of embryonic macrophages," she said. "How else are they different? Does one population specifically colonize specific organs but not others?"
Knowing there are two distinct versions of embryonic macrophages, only one of which is effective for tissue repair, could also provide critical insight into ongoing efforts to synthetically generate the white blood cells for medical uses. Though they're not in wide clinical use, researchers can produce macrophages in a lab—a technology that holds promise as a treatment for tissue repair and regeneration.
What's next
It will take years of additional research before the study's findings could lead to new options for leukemia treatment, a development that would be driven by interest from the pharmaceutical industry, Espin Palazon said.
"It usually takes a decade or more to go from the discovery side to clinical treatment, but you need to determine how our cells are doing what they are doing before you know what to manipulate to cure devastating diseases like leukemia. Otherwise, how are you going to know what to target?" she said.
More information: Abbigail McCune et al, Synergistic cooperation between progranulin and Jak2/Stat3 signaling determines definitive myeloid cell fate, Cell Reports (2026). DOI: 10.1016/j.celrep.2026.117477
Provided by Iowa State University
This story was originally published on Medical Xpress.
