April 14, 2024

New Study Sheds Light on Why Leukemic Stem Cells Survive Chemotherapy and How Growth Can Be Blocked

Researchers from the University of Birmingham, Newcastle University, and the Princess Maxima Center of Pediatric oncology have made groundbreaking discoveries about why myeloid leukemia relapses after chemotherapy and how growth can be halted with repurposed drugs. The findings, published in Nature Communications, have the potential to improve treatment outcomes for patients with acute myeloid leukemia (AML).

AML patients have a small population of leukemic stem cells (LSCs) in their bone marrow that are not affected by chemotherapy. After treatment, these dormant cells suddenly start to grow and produce AML cells, but the trigger for this growth was previously unknown.

The team of researchers conducted a study focusing on t(8;21) AML, a specific type of blood cancer. They analyzed single cells from patients with this type of leukemia to determine the factors that stimulate the growth of LSCs.

Professor Constanze Bonifer, who led the study, explained that leukemic stem cells are typically dormant and thus unaffected by chemotherapy. However, the researchers hypothesized that something must activate their growth for the leukemia to recur.

Using gene expression analysis in single LSCs, the researchers discovered that genes associated with growth regulation, normally not present in myeloid cells, were being expressed in these cells. These growth regulators included the receptor for VEGF signaling called KDR, which is typically found in blood vessels, and the IL-5 receptor, which is usually present on eosinophils. Interestingly, the leukemia cells themselves were also found to express VEGFA, the growth factor that binds to KDR and triggers its own growth.

To confirm their findings, the researchers activated these receptors in the laboratory and successfully induced stem cell growth. They also demonstrated that growth could be blocked in both cell cultures and mice by using existing drugs targeting VEGF (Avastin) and IL-5 signaling (Fasenra), which have been approved for other diseases.

Professor Olaf Heidenreich noted the importance of their discovery, highlighting the fact that the expression of these receptors is specific to t(8;21) AML, which is caused by a particular disease-causing mutation. This mutation leads to the production of the onco-fusion protein RUNX1::ETO, which reprograms the gene regulatory network responsible for the cells’ response to external growth signals.

The study’s first author, Dr. Sophie Kellaway, expressed excitement over the identification of two potential targets for preventing relapse in t(8;21) AML patients. However, she emphasized that these targets are specific to this particular type of leukemia and may not be applicable to other forms.

The researchers also mentioned that their analysis of other single-cell data from different leukemia subtypes suggests that other growth regulatory pathways are upregulated in stem cells of those subtypes as well. They hope to identify similar targets for other types of AML in future studies.

Dr. Suzanne Rix from Blood Cancer UK highlighted the significance of the research, stating that AML is an aggressive form of blood cancer that often relapses even after successful initial treatments. The findings provide insight into why relapse occurs in a specific type of AML and offer hope for developing new treatments to prevent recurrence. However, further research is needed to explore the potential application of this approach to other forms of AML. Additionally, more research is urgently required to develop effective and gentler treatments for all blood cancers.

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1. Source: Coherent Market Insights, Public sources, Desk research
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