Chronic myeloid leukemia (CML) is a blood cancer caused by a single genetic mutation in bone marrow stem cells. For over two decades, tyrosine kinase inhibitors (TKIs) have been the primary treatment for CML, specifically targeting cancerous cells. While TKIs have changed how CML is treated and improved survival rates, not all patients experience the same level of success. Some struggle to achieve remission, and the reasons for this variability have remained unclear. But now, a new study offers new insights into this phenomenon.
The study, led by first author and doctoral student Rebecca Warfvinge and supervised by Göran Karlsson of the Stem Cells and Leukemia Research Group at the Lund Stem Cell Center, sought to explore why these differences in treatment response occur. “In CML, every patient has the same genetic mutation, but their reactions to treatment can vary,” explains Göran Karlsson, Associate Professor in the Division of Molecular Hematology at Lund University. “We wanted to understand what’s happening at the stem cell level to see if we could uncover why.”
How to Tell Cancerous Stem Cells from Healthy Ones
Using advanced single-cell multiomics technology, Rebecca Warfvinge together with the research team analyzed blood samples from CML patients at diagnosis and compare these to patient outcomes after 12 months of treatment. Their goal was to compare the stem cell populations of patients who responded well to TKI treatment with those who did not.
One of their discoveries was the identification of two different stem cell markers: CD26+, found on leukemic (cancerous) cells, and CD35+, a marker unique to healthy, normal stem cells. By analyzing these markers, the researchers could see a clear distinction between the cells driving the leukemia and those involved in restoring normal hematopoiesis (blood development) during remission.
“What’s particularly exciting is the discovery of CD35+ as a unique marker for normal stem cells in CML patients,” says Göran Karlsson. “Previous markers weren’t specific enough because they were also found on cancerous cells. But by combining CD26+ and CD35+, we can now clearly distinguish between healthy and leukemic cells using simple lab methods like FACS analysis, which many diagnostic labs already use.”
Why Do Some Patients Fail to Respond?
The study also revealed that treatment outcomes were closely linked to the number of healthy stem cells patients had at diagnosis. Patients who responded poorly to TKI treatment had significantly fewer normal CD35+ stem cells in the blood and bone marrow at diagnosis, while their leukemic CD26+ stem cells were more prevalent. In contrast, patients who responded well had a reserve population of healthy stem cells ready to restore normal blood formation and initiate remission after the leukemic cells were suppressed by the TKIs.
“Our data indicate that in patients with fewer normal stem cells, once we wipe out the leukemia, there’s no healthy reserve to take over blood production,” Göran Karlsson explains. “This leaves them vulnerable to slow recovery, or relapse. It’s not just about destroying the cancerous cells—it’s also about ensuring the patient’s healthy cells can recover and rebuild the blood system.”
These findings suggest that the ratio of healthy to leukemic stem cells at diagnosis could serve as a predictive tool for treatment outcomes. “Imagine being able to take a simple blood test at diagnosis and predict whether a patient will respond well to standard TKI therapy,” Karlsson says. “For those with low numbers of healthy stem cells, we could potentially skip months of ineffective treatment and move straight to more aggressive therapies.”
Towards Treating CML with a Patient-Tailored Approach
The study is part of a larger clinical trial involving patients from across the Nordic countries, conducted in collaboration with the Nordic CML Study Group. While the results are promising, the researchers emphasize that further studies are needed to confirm the full potential of these findings.
“This is the first study to directly emphasize this connection between healthy stem cells and treatment response, but we need to validate it across larger patient groups,” says Göran Karlsson. “So far, the data looks solid, but we have to carefully measure if this method performs better than existing prognostic models, or adds to them.”
Looking ahead, the research team is committed to continuing their investigation and making their data openly available to the broader scientific community. “We believe in transparency,” Göran Karlsson emphasizes. “All of our data is accessible through open-access platforms like eLife and Nygen Database, so other researchers can build on what we have discovered. Open collaboration is crucial to advancing our understanding of diseases like leukemia.”
This research is a step forward in understanding why CML patients respond differently to treatment and highlights how therapies could be better tailored to individual needs. As Göran Karlsson puts it: “The key to improving outcomes may not just lie in targeting the leukemic cells, but in ensuring the normal stem cells are strong enough to take their place.”
