Scientists from the German Cancer Research Center and HI-STEM have uncovered a major reason why acute myeloid leukemia (AML) frequently returns after treatment. Their findings, published in Cell Stem Cell, reveal that leukemia stem cells, the rare but critical cells that sustain the disease, exist in multiple biologically distinct forms, each with different vulnerabilities and resistance mechanisms.
The discovery helps explain why venetoclax, one of the most important targeted therapies in AML, often loses effectiveness over time. More importantly, it provides a framework for designing personalized combination therapies that could prevent relapse by targeting resistant stem cell populations before they expand.
Why AML remains difficult to cure
Acute myeloid leukemia is an aggressive blood cancer characterized by the rapid accumulation of abnormal myeloid cells in the bone marrow. Although newer targeted therapies have improved outcomes, relapse remains the central clinical challenge.
One of the most transformative advances in AML treatment has been the introduction of venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2. Combined with hypomethylating agents or low-dose chemotherapy, venetoclax has substantially improved responses, particularly in older patients who are unable to tolerate intensive chemotherapy.
Yet despite these advances, most patients eventually relapse.
Researchers have long suspected that leukemia stem cells are responsible. These rare cells possess the ability to self-renew indefinitely and survive therapeutic pressure, allowing the disease to regenerate even after apparently successful treatment.
Not one leukemia stem cell—but four
In the new study, researchers analyzed samples from more than 150 AML patients to better understand how leukemia stem cells respond to therapy.
Their findings challenge the idea that AML stem cells represent a single uniform population. Instead, the team identified at least four distinct leukemia stem cell subtypes, each resembling different developmental stages of normal blood cell formation.
This developmental identity turned out to be critically important because it determined which survival pathways the cells depended on—and therefore how sensitive they were to venetoclax.
Some stem cell subtypes were highly dependent on BCL-2 and responded well to treatment. Others relied on alternative survival programs that rendered them intrinsically less sensitive to the drug.
Cancer stem cells adapt under therapeutic pressure
One of the study’s most significant findings was that leukemia stem cells are not fixed in a single state. Instead, they can dynamically reprogram themselves in response to therapy.
Venetoclax works by blocking BCL-2, a protein that protects leukemia cells from programmed cell death. When BCL-2 is inhibited, susceptible leukemia cells undergo apoptosis.
However, the researchers found that under treatment pressure, many leukemia stem cells transition into more resistant cellular states. Rather than relying on BCL-2, these resistant cells switch to using a related survival protein known as BCL-xL.
This adaptive shift effectively allows the cells to bypass venetoclax and survive treatment.
The findings strengthen a broader principle increasingly recognized across oncology: cancer is not only genetically heterogeneous but also highly plastic. Tumor cells can alter their identity to evade therapeutic pressure, making durable treatment responses difficult to achieve with single-agent therapies.
Combination therapies may overcome resistance
The study also points toward potential strategies for overcoming this resistance.
By identifying which survival pathways individual leukemia stem cell subtypes depend on, researchers showed that resistant populations could potentially be targeted with rational drug combinations. In particular, combining venetoclax with inhibitors targeting BCL-xL emerged as a promising approach.
In mouse models transplanted with patient-derived leukemia cells, these subtype-specific combination therapies were significantly more effective than current standard approaches.
This suggests that future AML therapy may require simultaneous targeting of multiple stem cell states to prevent resistant populations from emerging during treatment.
Biomarkers could guide precision medicine in AML
Another key advance from the study was the identification of biomarkers capable of distinguishing the different leukemia stem cell subtypes.
These biomarkers could eventually enable clinicians to determine, at the time of diagnosis, which resistance mechanisms are most likely to arise in a particular patient.
“This means that in the future, it may be possible to determine at the time of diagnosis which patient will benefit most from which therapy,” said Alexander Waclawiczek, PhD, first author of the study.
Such an approach would represent a major shift away from treating AML as a largely uniform disease and toward truly individualized therapy guided by stem cell biology.
A new framework for AML treatment
The findings also reinforce the growing importance of cancer stem cell biology in therapeutic design. Rather than focusing exclusively on eliminating bulk tumor cells, future strategies may increasingly aim to eradicate the specific stem cell populations capable of regenerating disease after therapy.
“The results should help to align AML therapy in the future more closely with the biological characteristics of individual AML cases and, in particular, their leukemia stem cells, rather than treating all patients according to a similar protocol,” said Andreas Trumpp, PhD, who led the study.
The next major step will be translating these findings into clinical trials testing personalized combination therapies tailored to leukemia stem cell subtype composition.
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