In more aggressive forms of leukemia, blood cell factories in the bone marrow become stuck. Instead of dividing and multiplying at the usual prolific pace, generating hundreds of billions of new cells daily, some progenitor cells stop at an immature stage.
Image of human leukemia cells taken by Raquel Espin Palazon, associate professor of genetics, development and cell biology at Iowa State University. A research team led by Espen Palazón has discovered two elements essential to the formation of some types of white blood cells, which could lead to a new treatment option for some leukemia patients. Image source: Raquel Espin Palazón/Iowa State University.
“It never ends. It never becomes what it should be,” said Raquel Espin Palazon, associate professor of genetics, development and cell biology at Iowa State University. “Because they are progenitor cells, they have no real function and they just expand and collapse our bone marrow.”
New findings by a research team led by Espen Palazón have identified two key components — a ubiquitinated protein and a crucial cell signaling pathway — that are necessary for making some types of blood cells, a discovery that could lead to a new treatment for blood cancer.
Mysterious protein levels
the He studiespublished last month in the journal Cell Reports, arose from researchers’ interest in progranulin, a protein found in most plants and animal bodies that plays a role in cell growth, tissue repair, and inflammation. They wanted to know why progranulin was the most highly expressed gene in human macrophages, the large white blood cells that engulf and eliminate pathogens.
“No one has linked a function in macrophages to this protein,” Espin Palazón said. “But there must be some reason why it is so highly expressed.”
Progranulin is difficult to study directly in mammalian macrophages, which carry a single gene for protein production throughout their bodies. If scientists turned off this gene, the effects would be too broad and interconnected to pinpoint what is happening in the blood cells. But there are two types of progranulin in zebrafish, which is a popular research topic for human health He studied often By Espen Palazon and other Iowa State scientists.
In a He studies Published in 2021 A team led by Espen Palazón showed that one of the progranulin genes in zebrafish is expressed only in blood cells. The researchers found that 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.
To see if progranulin also triggers myeloid maturation in humans, researchers tried different ways to add it to human leukemia cells. If the protein can make human myeloid cells differentiate into mature white blood cells, it could be a promising treatment for leukemia. At first, it didn’t work.
The second required item
To dig deeper, the researchers returned to zebrafish that had been modified to lack the type of progranulin found in blood cells. They analyzed other errors that occurred when progranulin disappeared from blood cells. One notable defect was a pathway called JAK2/STAT3, which uses chemical signals to deliver information from outside the cell to the DNA in its nucleus. Both progranulin and JAK2/STAT3 were necessary for the transformation of myeloid progenitors into macrophages.
JAK2/STAT3 is often overactivated in a variety of cancers, including leukemia. Adding progranulin to leukemia cells that have an active JAK2/STAT3 pathway causes them to mature, allowing the cells to progress through their usually short-lived life cycle and eventually die, Espin Palazón said.
“It was very exciting to see this differentiation, and to overcome this blockage in the human leukemia line,” she said. “Adding progranulin, the missing ingredient, could be a potential therapeutic target.”
The discovery of both essential components of myeloid differentiation is an example of why it is beneficial to study living organisms rather than isolated cells, Espen Palazón said.
“Animal models are sometimes necessary to drive discoveries, because they allow us to understand biology within the complexity of an intact organism, something lab-grown systems cannot yet fully reproduce,” she said.
A path to new research
Relevant findings included in the new study could also be useful in human health research.
Some macrophages in embryos develop and become specialized, living a lifetime and self-renewing in a particular major organ such as the brain or heart. Espin Palazón’s team found that there are two types of embryonic 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, she said.
“This opens up possibilities for studying and dissecting the two different types of embryonic macrophages,” she said. “How do these populations differ? Does a particular population specifically colonize certain organs and not others?”
Knowing that there are two different versions of fetal macrophages, only one of which is effective for tissue repair, could also provide important insight into ongoing efforts to generate white blood cells artificially for medical uses. Although not in widespread clinical use, researchers can produce macrophages in the laboratory, a technology that shows promise as a treatment for tissue repair and regeneration.
What’s the next step?
Espin Palazon said it will take years of additional research before the study results lead to new options for treating leukemia, a development that may be driven by interest from the pharmaceutical industry.
“It usually takes a decade or more to go from the discovery side to clinical treatment, but you need to determine how our cells do what they do before you know what to address to treat devastating diseases like leukemia. How else will you 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 Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases, one of the National Institutes of Health.
source: Iowa State University
