Hedy Tung

In a recent study, Yale researchers discovered a new molecule that can temporarily boost white blood cell counts. 

The study, led by Nikolai Jaschke, a postdoctoral researcher in the lab of Andrew Wang, an internal medicine professor at the School of Medicine, found that the introduction of A485 in mice offers a short-term but significant increase in white blood cell counts. A485 is a small molecule — colloquially known as “prohiberin” — that inhibits proteins that modulate gene expression. The researchers hope that the discovery could help human patients with neutropenia, or low white blood cell counts, which is common in those fighting infections and undergoing chemotherapy.

“At this point, from what we know in mice, it seems reasonable that a lot of patients receiving chemotherapy could benefit from this molecule,” Jaschke said. “But it’s not clear if that’s the case and it needs to be tested in clinical trials.”

Jaschke told the News that he first became interested in A485 after researchers from the pharmaceutical company AbbVie and other institutions first published a study in 2017 detailing how it could be used to treat various malignancies.

However, the research team never followed up on the study. A few years later, Jaschke and his team decided to study whether A485 could help restore bone marrow function, hoping to analyze the molecule from a pharmaceutical rather than oncological perspective. From a new scientific viewpoint, they discovered another use for A485.

“We kind of stumbled across [the discovery] in a very different context because we were interested in a pharmaceutical mechanism or pharmacological mechanism to restore bone marrow function,” Jaschke said.

Because many patients with bone marrow failure are more likely to have infections due to diminished white blood cell counts, the researchers explored whether the injection of A485 molecules could help save mice suffering from myelodysplastic syndrome, a group of cancers in which blood cells in the bone marrow don’t properly develop, and chemotherapy-induced bacterial infections, some of which were potentially lethal. 

They found that almost a third of the mice treated with A485 therapy survived, suggesting its potential use as a therapeutic intervention. Jaschke argued that there is currently no available pharmacological remedy with similar capabilities to what A485 expressed in his team’s mouse model.

Jaschke compared the A485 molecule with G-CSF, a glycoprotein hormone that stimulates the bone marrow to increase the number of white blood cells in the bloodstream. He noted that while many doctors prescribe G-CSF to patients undergoing chemotherapy, many still experience low blood counts and subsequent infections. Once they are reinfected, their treatment options are limited to antibiotics, fluids and supportive care.

Lourdes Mendez, assistant professor of hematology at the School of Medicine, is dedicated to both the clinical care of patients and translational research to identify novel therapeutics in high-risk myeloid neoplasms and leukemia to improve clinical outcomes for patients. She told the News, “Neutropenic fever and sepsis remain a critical problem in our field particularly for patients with acute leukemia. This study on A485 raises the exciting possibility that our toolbox, which is currently limited to G-CSF, could expand by targeting p300 HAT activity.”

In contrast, the A485, Jaschke said, could be used in concert with G-CSF to help increase white blood cell counts. Though A485 is a synthetic molecule, it does not need stem cells to proliferate, unlike G-CSF. 

Still, other researchers are cautiously optimistic about the study and A485’s future. In an interview with the News, Andres Hidalgo, a professor of immunobiology at the School of Medicine, noted that the study was conducted with mouse models and was not tested directly next to G-CSF.  

“If [A485] is better than G-CSF, I think that might be a little bit of an overstatement at this point,” Hidalgo said. 

Similarly, Jaschke said that he is unsure whether the promising results will be replicated in future experiments in human subjects. 

“I have no idea if it will even provoke the same effects in humans as it did in mice,” Jaschke said. “This needs to be tested and this needs to be seen, which requires clinical studies, which are very expensive. I don’t know if someone will look into this.”

Jaschke also highlighted several other challenges with their investigation. First, he noted that while the molecule responded effectively to the bacteria Listeria, researchers need to conduct further testing to determine the molecule’s efficacy against other common pathogens, such as pneumococci, staphylococci and E. coli, among others.

He also expressed concerns about the consequences of a potential excessive immune response due to the significant increase in white blood cells induced by the molecule. Jaschke compared the strong immune response to immune checkpoint inhibitors, a set of immunotherapies that are often used in cancer treatment but can sometimes lead to an overly robust immune response. 

He lastly conveyed that they have extensively characterized the compound, addressing many important questions regarding its efficacy and safety. They believe that further confirmation through testing in various models by different laboratories is necessary to validate their findings, particularly regarding the compound’s effectiveness against a wide range of pathogens and in different models of bone marrow injury.

Lohith Gowda, an assistant professor of hematology at the School of Medicine, raised concerns about A485 beyond its safety.

He also discussed the effects of prolonged neutropenia and whether it can lead to altered immunity. 

“Can A485 alter or interact differently with microbiomes?” Gowda questioned. “Can [it] help build a different story if favorable?”

Jaschke also emphasized the need for other laboratories to validate their findings and learn more about the safety and efficacy of the compound in humans. Nevertheless, his lab does not plan on conducting further research with the molecule in the near future.

“That’s not something that we will do necessarily because we have described what we found,” Jaschke said. “From that perspective, we are done.”

About 35.5 million individuals in the United States suffer from neutropenia.