Each year in Sweden, around 350 adults are diagnosed with acute myeloid leukemia (AML), an aggressive form of blood cancer. One of the biggest challenges in treating AML is relapse, despite initial responses to therapy, the disease often returns. This happens because a small population of treatment-resistant cancer cells, known as leukemia stem cells, survives and allows the cancer to resurface.
Researchers in the Targeted Therapies in Leukemia Research Group, led by Associate Professor Marcus Järås, are working to understand how these stem cells evade immune detection. Their goal is to develop targeted treatments that can eliminate them.
Their latest study builds on their previous findings, particularly a 2023 publication in Blood Advances that used CRISPR-Cas9 screening to identify genetic vulnerabilities in leukemia stem cells. One gene, H2-k1, stood out. Initially, the team set out to investigate its role in leukemia stem cell survival, but their findings took an unexpected turn.
"We found that as soon as we knocked out or downregulated the H2-k1 gene, leukemia stem cells were completely eliminated in our mouse models. The mice also survived with a normal lifespan," explains Somadri Ghosh, first-author and a postdoctoral researcher at Lund University.
This led the researchers to a critical question: How were the leukemia cells disappearing so efficiently? Which immune cells were playing a role?
Leukemia’s Defense Mechanism
By analyzing different immune cells, the team discovered that NK cells were the key players in leukemia clearance. NK cells usually help destroy infected and cancerous cells in the body, but the researchers found that the leukemia cells were actively suppressing their function.
"We realized that the leukemia cells were altering NK cells—specifically, their maturation and ability to kill," says Somadri. "Essentially, the leukemia cells were suppressing the immune system’s response to protect themselves."
The study showed that in mice with AML driven by the MLL-AF9 oncogene, leukemia stem cells express H2-K1 to manipulate NK cells. This prevents the NK cells from fully maturing and weakens their ability to attack the cancer cells, allowing them to evade the immune system’s defenses.
"When we removed H2-k1 on the leukemia cells, the NK cells reverted to their normal function, and the immune system could effectively eliminate the leukemia," he adds.
Their findings give us a new understanding of how cancer stem cells can trick the immune system, making it harder for the body to identify and fight them. "This is the first time we have mapped out how leukemia stem cells rewire NK cell function via the H2-k1-ligand interaction," says Somadri Ghosh. "Understanding this pathway is important, as it may help us develop new therapies that restore immune function."
Finding a way to selectively target leukemia stem cells
The discovery is an important step forward in understanding how leukemia rewires the immune system. Though there is still more work to be done before these findings can be used in a clinical setting.
"One of the biggest issues in the field right now is that what works in mouse models does not always translate directly to human settings," Somadri Ghosh cautions. "In humans, NK cells have been found to not be as effective as they are in mice. Instead, macrophages seem to play a bigger role in immune surveillance."
Macrophages, another type of immune cell, are part of the body's first line of defense. These cells can engulf and destroy pathogens, remove dead cells, and signal other immune cells—such as NK cells—to attack cancer.
"What role macrophages might play in this process is something that we are currently looking into with follow-up studies in human leukemia cells," he notes. "Although the challenge with H2-k1, and related MHC Class 1 molecules, are that they are expressed on most cell types in the body, not just leukemia cells
The team is now investigating whether a more selective target exists, that when targeted, can affect MHC class I expression specifically on the leukemia cells. "The ultimate goal is to find a way to selectively target leukemia stem cells while sparing healthy ones. That’s where our focus lies," concludes Marcus Järås, associate professor at the Department of Clinical Genetics.
