In the most aggressive forms of leukemia, blood cell factories in the bone marrow malfunction. Rather than dividing and proliferating at their normal prolific pace, producing hundreds of billions of new cells every day, some progenitor cells stall at an immature stage.
they never end. They are never what they should be. Since these are progenitor cells, they don’t actually have any function, they just expand or collapse the bone marrow. ”
Raquel Espin-Palazon, Associate Professor of Genetics, Developmental and Cell Biology, Iowa State University
A new discovery by a research team led by Espin Parazon identifies two essential components needed to make certain types of blood cells: a permeability protein and a key cell signaling pathway, and could lead to new treatments for leukemia.
puzzling protein levels
This study was published last month. cell reportwas born out of researchers’ interest in progranulin, a protein found in most plants and animals that plays a role in cell growth, tissue repair, and inflammation. They wanted to know why progranulin is the most expressed gene in human macrophages, large white blood cells that engulf and eliminate pathogens.
“No one had ever linked this protein to macrophage function, but there must be a reason why it is so highly expressed,” Espin-Parazon said.
Directly studying progranulin in macrophages is difficult in mammals, which have a single gene for producing the protein throughout the body. When scientists turn off that gene, the effects are too far-reaching and interconnected to pinpoint exactly what’s happening in the blood cells. But zebrafish have two types of progranulin, and they are a common subject of human health research, frequently studied by Espin-Palazon and other Iowa State scientists.
In a study published in 2021, a research team led by Espin Parazon showed that one of the zebrafish progranulin genes is expressed only in blood cells. The researchers found that the production of this protein is important because it is required for precursor cells called myelocytes to develop into white blood cells such as macrophages and neutrophils.
To see if progranulin also promotes bone marrow maturation in humans, the researchers tried different ways to add progranulin to human leukemia cells. If this protein can induce human bone marrow cells to differentiate into mature white blood cells, it may hold promise as a treatment for leukemia. It didn’t work at first.
Requires second material
To dig deeper, the researchers returned to zebrafish that had been engineered to lack a type of progranulin found in blood cells. They analyzed what else went wrong when blood cell progranulin ran out. One notable defect is in a pathway called JAK2/STAT3, which uses chemical signals to transmit information from outside the cell to DNA in the nucleus. Both progranulin and JAK2/STAT3 were essential for the transformation of bone marrow progenitors into macrophages.
JAK2/STAT3 is often overactivated in various cancers, including leukemia. Adding progranulin to leukemia cells in which the JAK2/STAT3 pathway is active allows the leukemia cells to mature and eventually die after a normally short-lived life cycle, Espin-Parazon said.
“It was very exciting to see differentiation, the barrier to human leukemia lineage, being overcome,” she said. “Adding the missing component, progranulin, could be a potential therapeutic target.”
Elucidating both components essential for myeloid differentiation is an example of why studying living subjects rather than isolated cells is beneficial, Espin-Palazon said.
“Animal models are sometimes essential for facilitating discovery because they allow us to understand biology in the complexity of intact organisms, which cannot yet be fully reproduced in lab-generated systems,” she said.
The road to new research
Related findings in the new study may also be useful for human health research.
Some macrophages develop in the embryo and become specialists, residing throughout their lives in certain major organs such as the brain and heart, where they self-renew. Espin Palazon’s team discovered that there are two types of embryonic macrophages, but only one requires the JAK2/STAT3 pathway and progranulin for its formation. Embryonic macrophages, which require both components, are better able to regenerate tissue to heal injuries, she said.
“This opens up the possibility of studying and dissecting two different types of fetal macrophages,” she said. “What other differences are there? Some populations specifically colonize certain organs, while others don’t?”
Knowing that there are two different versions of embryonic macrophages, only one of which is effective in tissue repair, may also provide important insights in ongoing efforts to synthetically generate white blood cells for medical applications. Although not widely used in the clinic, researchers can generate macrophages in the lab. This technology holds promise as a treatment for tissue repair and regeneration.
what’s next
Espin-Palazon said it will take many more years of research before the findings lead to new options for treating leukemia and interest from the pharmaceutical industry drives their development.
“It typically takes more than a decade to go from discovery to clinical treatment, but before we can know what to manipulate to cure a devastating disease like leukemia, we need to determine how the cells are doing. Otherwise, how would we know what to target?” she said.
The study included collaborators from Children’s Hospital of Philadelphia and the University of Salamanca in Spain. Support for the research included grants from the Roy J. Carver Charitable Trust and the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health.
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Reference magazines:
McCune, A. Others. (2026). The synergistic cooperation between progranulin and Jak2/Stat3 signaling determines the ultimate myeloid cell fate. cell report. DOI: 10.1016/j.celrep.2026.117477. https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00555-3
