The mystery of why myeloid leukemia begins to grow again after chemotherapy kills most malignant cells and how to prevent growth through reused drugs may be solved through new research.
The bone marrow of patients with acute myeloid leukemia (AML) contains a rare group of leukemia stem cells (LSCs) that do not grow and therefore are not killed by chemotherapy. However, after treatment, these cells began to grow and produce AML cells, but it is currently unclear what initiated this process.
In a new study, researchers from the University of Birmingham, Newcastle University, and Princess Maxima Pediatric Oncology Center in the Netherlands studied individual cells in patients with t (8; 21) acute myeloid leukemia (a special type of blood cancer) to explore what drives rare LSC growth. The relevant research results were published in the journal Nature Communications, with the title “Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth”.
Professor Constanze Bonifer, co-author of the paper and researcher at the Institute of Cancer and Genomics at the University of Birmingham, said, “LSCs often appear to be in a dormant state, which is why they are not killed by chemotherapy. These cells are very rare and difficult to study, but by studying the gene expression of individual LSCs, we found that some genes are being expressed, and the growth regulatory factors encoded by these genes are usually not present in myeloid cells. These two cell types exist together with AML cells in the bone marrow, but healthy stem cells do not respond to their signals. By abnormally up-regulating these growth regulatory factors, LSCs can now respond to the growth factors present in the body that tell them to grow.”
The growth regulatory factors identified in this new study are the VEGF signaling receptor KDR, which is typically only expressed in blood vessels, and the IL-5 receptor, which is typically only expressed on the surface of eosinophils. In addition, the growth factor VEGFA, which binds to KDR, is also expressed in this type of leukemia, indicating that it can induce its own growth.
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After identifying these receptors, these authors confirmed that by activating them in the laboratory, they can trigger stem cell growth. Importantly, they also found that by reusing the drug targeting vascular endothelial growth factor – Avastin, which has been approved for use in various solid tumors, including colorectal cancer, and the drug targeting IL-5 signaling – Fasenra, growth can be inhibited in culture dishes and in mice.
Professor Olaf Heidenreich, co-author of the paper and from Newcastle University and Princess Maxima Children’s Oncology Center, said, “An exciting result of this new study is that the expression of these receptors is unique to this particular type of leukemia.”. The expression of these receptors is the result of a specific pathogenic mutation that produces the oncogenic fusion protein RUNX1: ETO, which reprograms the gene regulatory network that determines how cells respond to external growth signals. This new study highlights the powerful role of single-cell analysis in delving deeper into the regulatory mechanisms of AML cell growth. It also highlights the fact that AML subtypes may have to be treated as independent entities.
Dr. Sophie Kellaway, the first author of the paper, said, “We are very excited to discover two new targets that could be used to prevent recurrence in these patients. Knowing that cancer recurrence in the body is a devastating news, we hope to prevent this from happening. Unfortunately, due to the strong specificity of these receptors, this can only be effective for t (8; 21) acute myeloid leukemia and is not a panacea. However, examination of single-cell data from different subtypes of leukemia shows that there are also other growth regulatory pathways upregulated in their stem cell populations. We now hope to find those pathways that can be hit in other types of AML.”
Dr. Suzanne Rix from the British Society for Blood Cancer said, “Blood cancer is the third-largest cancer killer in the UK, and AML is a highly invasive form of blood cancer that can still recur even after initial treatment is successful. This new study reveals the causes of a specific type of AML recurrence, which may lead to the development of new therapies that may prevent the recurrence of this particular form of leukemia, bringing new hope to patients. However, further research is needed to determine whether similar methods can be used for other forms of AML, and more broadly, more research is urgently needed to develop effective and friendlier treatment methods for all forms of blood cancer.”
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Reference
Sophie G. Kellaway et al. Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth. Nature Communications, 2024, doi:10.1038/s41467-024-45691-4.