The bone marrow is the central reservoir for leukocytes, which include specialized populations such as neutrophils, monocytes, and B lymphocytes. Although there are many studies of how leukocyte compartments are controlled, pharmacological interventions to interfere with the production, degradation, and localization of leukocytes to correct diseases of acute and chronic inflammation remain limited. Now, researchers have discovered in mice the small-molecule A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood.
Their findings are published in Immunity in the article titled, “Small-molecule CBP/p300 histone acetyltransferase inhibition mobilizes leukocytes from the bone marrow via the endocrine stress response.”
“Mutations of the CBP/p300 histone acetyltransferase (HAT) domain can be linked to leukemic transformation in humans, suggestive of a checkpoint of leukocyte compartment sizes,” the researchers wrote. “Here, we examined the impact of reversible inhibition of this domain by the small-molecule A485. We found that A485 triggered acute and transient mobilization of leukocytes from the bone marrow into the blood.”
The researchers observed the effect A485 had on blood cells in mice. The molecule, which the researchers have proposed calling “prohiberin,” inhibits proteins that modulate gene expression.
“We found that this molecule, A485, provoked a strong increase in white blood cells, including those involved in both the adaptive and innate immune systems,” said Nikolai Jaschke, PhD, lead author of the study and a postdoctoral fellow in the lab of Andrew Wang, MD, PhD, associate professor of internal medicine (rheumatology) and of immunobiology at Yale School of Medicine.
This increase in white blood cells, deployed from the animals’ bone marrow, occurred shortly after exposure to A485. About 12 hours later, the researchers said, cell counts dropped back to previous levels. This short-term effect is key, said Jaschke.
“Currently, the main treatment for low white blood cell counts is G-CSF, or granulocyte colony-stimulating factor, which is produced by the body and can be administered as a drug,” said Jaschke. “But it has a long-lasting effect, which can be harmful in some circumstances, limiting its wider clinical use. A485 is just as potent as G-CSF but less enduring.”
The researchers gave A485 to mice that had received chemotherapy to see if this brief increase in white blood cells might be effective in treating infection. Even with damaged bone marrow, mice that received A485 survived at higher rates than those that did not.
“When patients develop low white blood cell counts after chemotherapy, a condition called neutropenic fever, antibiotics are the only approved therapy,” said Jaschke. “A485 could be another option.”
Going forward, Jaschke noted more research needs to be done to better understand how A485 has the effect that it does. But the current study offers some clues.
Jaschke and his colleagues found that A485 works, in part, through endogenous G-CSF, which is a protein that stimulates the bone marrow to make more blood cells. They also found that combining G-CSF and A485 produced an additive effect on white blood cell mobilization that could be beneficial as a treatment.
The study also revealed that A485 activates what’s known as the body’s “stress axis,” engaging a hormone that, until now, was believed to only regulate levels of another hormone, cortisol.
“But we found that this hormone can regulate neutrophils, which opens up a whole new field of questions,” said Jaschke. “Along with A485 working through G-CSF, these findings mean there are pathways that mediate bone marrow mobilization that we don’t even know about yet.”