A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth

In the human body, the bone marrow acts as a factory, constantly churning out new blood cells to replace those that age or die. This process is tightly regulated by a complex network of signals, some of which are triggered by inflammation. When the body fights an infection, immune cells release chemical messengers called cytokines, including one known as interferon-gamma. In a healthy system, this molecule helps coordinate the defense, often telling stem cells—the master cells that can become any type of blood cell—to pause their work and wait for the danger to pass. However, in acute myeloid leukemia, a fast-growing cancer of the blood, the story is far more complicated. The disease is driven by a small group of rogue stem cells that can restart the cancer even after treatment. Scientists have long wondered how these cancer cells react when the body's immune system tries to fight them with inflammation. Does the inflammatory signal kill the cancer, or does it somehow help the cancer hide and survive?

A team of researchers set out to answer this question by looking directly at human leukemia cells and testing them in mice. They focused on what happens when these cancer cells are exposed to interferon-gamma, a key signal of inflammation. Their work reveals a surprising dual reaction: the cancer cells do not simply die or simply grow. Instead, the inflammatory signal forces the leukemia to split into two distinct paths at the same time. One group of cells, the most dangerous ones capable of regenerating the entire disease, retreats into a deep, dormant state, effectively hiding from the immune system and chemotherapy. At the same time, the other group of cells, which are more mature and less dangerous, begins to divide rapidly but then dies off quickly. This mechanism allows the cancer to survive the initial attack of the immune system and eventually bounce back.

The researchers began by taking samples of leukemia from patients and growing them in a lab dish. They treated some of these cells with interferon-gamma and others with a harmless salt solution as a control. Using advanced technology that allows scientists to read the genetic activity of thousands of individual cells at once, they mapped out what the cells were doing. They found that the cells treated with the inflammatory signal changed their behavior in a very specific way. The cells that looked like the most primitive stem cells became even more primitive, entering a state of deep rest. These are the cells that can start a new leukemia in a new host. Meanwhile, the cells that were slightly more mature, which usually act as the working force of the cancer, started to divide faster. However, this rapid division came at a cost. These fast-dividing cells produced offspring that were fragile and died off quickly, leading to a net loss in the number of these specific cells.

To understand if this was just a random reaction of different cells or a coordinated strategy by the cancer, the researchers looked at the genetic fingerprints of the cells. Every cell carries tiny mutations in its mitochondrial DNA, which act like natural barcodes. By tracking these barcodes, the scientists could see which cells were related to each other, essentially following family lines. They discovered that even within a single family of cancer cells, the response was split. Some members of the same family retreated into the deep, protective dormancy, while other members of the same family rushed to divide and then died. This means the cancer does not rely on having some cells that are naturally resistant and others that are weak. Instead, a single clone of cancer cells can adapt to the inflammatory threat by splitting its own fate: preserving the most dangerous stem cells while sacrificing the more expendable ones.

The team then moved from the lab dish to living mice to see if this phenomenon happened in a real body. They created a model of leukemia that could be recognized by the mouse's own immune system. When they injected these cancer cells into mice with working immune systems, the immune response generated its own interferon-gamma. As predicted, the number of primitive cancer cells in the mice dropped initially, suggesting the immune system was having an effect. However, when the researchers took the remaining cancer cells from these mice and put them into new mice, the cancer grew back just as strongly as it did in mice without immune systems. This proved that the few cancer stem cells that survived the inflammatory attack had not been weakened. In fact, they had become even more potent at regenerating the disease. The inflammatory signal had temporarily reduced the size of the cancer, but it had also selected for the cells that were best at surviving and restarting the disease later.

This finding helps explain why leukemia often returns after treatment, even when the initial therapy seems successful. Many standard treatments, including chemotherapy and immunotherapy, work by creating inflammation or by directly killing dividing cells. The study suggests that while these treatments may kill the bulk of the cancer, they might inadvertently push the most dangerous stem cells into a deeper state of rest. Once the inflammation subsides, these hidden cells can wake up and rebuild the tumor. The researchers observed this pattern across different types of leukemia from various patients, indicating that this is a common survival strategy for the disease.

The implications of this discovery are significant for how doctors might approach treatment in the future. If inflammation can drive cancer stem cells into a protective hiding spot, then simply adding more inflammation might not be enough to cure the disease. The study suggests that therapies need to be designed to catch these cells before they can retreat or to wake them up so they can be targeted while they are vulnerable. The researchers did not test new drugs in this study, but their work provides a clear map of how the cancer behaves under pressure. By understanding that the cancer splits its response—hiding the leaders while sacrificing the workers—scientists can begin to design strategies that prevent the cancer from using this split to its advantage. The goal is to stop the cancer from finding a way to survive the very signals meant to destroy it.