In the most aggressive forms of leukemia, the blood cell factories in our bone marrow falter. Instead of dividing and multiplying at their normal productive rate, creating hundreds of billions of new cells every day, some precursor cells are shed at an immature stage.
“They never end. They never become what they’re supposed to be. Because they’re progenitor cells, they don’t really have a function and they just expand and break down our bone marrow,” said Raquel Espin Palazon, an associate professor of genetics, developmental and cell biology at Iowa State University.
New findings from a research team led by Espin Palazon have identified two key components—a diffusible protein and a critical cell signaling pathway—that are required to make certain types of blood cells, a discovery that could lead to a new treatment for leukemia.
Incredible levels of protein
The study, published last month in Cell referencesarose from researchers’ interest in progranulin, a protein found in most plant 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 human macrophages, the large white blood cells that engulf and remove pathogens.
“Nobody had linked a function in macrophages to this protein. But there must be some reason it is so highly expressed,” said Espin Palazon.
Directly studying progranulin in macrophages is difficult in mammals, which carry a single gene for producing the protein throughout their bodies. If scientists turn off this gene, the effects are too far-reaching and interconnected to pinpoint what happens in the blood cells. But there are two types of progranulin in zebrafish, a common research subject in 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 the zebrafish progranulin genes is expressed only in blood cells. This production is important because the protein is necessary for progenitor cells called myeloid cells to develop into white blood cells such as macrophages and neutrophils, the researchers found.
To see if progranulin also led to marrow maturation in humans, the researchers tried different methods of adding it to human leukemia cells. If the protein could cause human myeloid cells to differentiate into mature white blood cells, it could hold promise as a leukemia treatment. At first, it didn’t work.
A second component is required
To dig deeper, the researchers returned to their altered zebrafish without the type of progranulin found in blood cells. They analyzed what else went wrong when the blood cell progranulin was gone. One major flaw was a pathway called JAK2/STAT3, which uses chemical signals to transfer information from outside a cell to the DNA in its nucleus. Both progranulin and JAK2/STAT3 were essential for the transformation of myeloid progenitors into macrophages.
JAK2/STAT3 is frequently overactivated in various cancers, including leukemia. Adding progranulin to leukemia cells that have an active JAK2/STAT3 pathway causes them to mature, allowing the cells to proceed through their typically short life cycle and eventually die, Espin Palazon said.
“It was extremely exciting to see the differentiation, this blockage in the human leukemia line being overcome,” he said. “Adding progranulin, the missing component, could be a potential therapeutic target.”
Identifying both components necessary for myeloid differentiation is an example of why it can be beneficial to study living individuals instead of isolated cells, Espin Palazon said.
“Animal models are sometimes essential to drive discovery because they allow us to understand the biology within the complexity of an intact organism—something that lab-created systems cannot yet fully reproduce,” he 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 life of self-renewal in a particular important organ such as the brain or heart. Espin Palazon’s team found that there are two types of fetal macrophages, only one of which requires the JAK2/STAT3 pathway and progranulin to form. Fetal macrophages that require both components are better at regenerating tissue to heal injuries, he said.
“This opens up possibilities for studying and dissecting the two different types of fetal macrophages,” he said. “How else do they differ? Does one population colonize certain specific organs but not others?”
Knowing that there are two different versions of fetal macrophages, only one of which is effective for tissue repair, could also provide critical insight into ongoing efforts to synthetically produce white blood cells for medical uses. Although not in widespread clinical use, researchers can produce macrophages in a lab—technology that holds promise as a therapy for tissue repair and regeneration.
What’s next
It will take years of additional research before the study’s findings lead to new options for treating leukemia, a development that will be driven by interest from the pharmaceutical industry, Espin Palazon said.
“It usually takes a decade or more to go from discovery to clinical treatment, but you have to determine how our cells do what they do before you know what to manipulate to treat devastating diseases like leukemia. Otherwise, how will you know what to target?” she said.
The study involved collaborators from the 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, one of the National Institutes of Health.
