New Target for Leukemia Therapy Identified – Leukemia, the most prevalent pediatric cancer, poses a significant challenge to children’s health. Current treatment options, primarily chemotherapy, are often accompanied by severe side effects due to their nonspecific targeting of both healthy and cancerous cells. Researchers at Goethe University Frankfurt have made a promising breakthrough in leukemia therapy by identifying a crucial gene, MYNRL15, that is essential for the survival of leukemia cells. This discovery opens up new avenues for developing targeted therapies that specifically eliminate leukemia cells while minimizing harm to healthy tissues.
Leukemia encompasses a spectrum of blood cancers, including acute myeloid leukemia (AML). In AML, blood cells in their early stages, such as stem cells and precursor cells, undergo a transformation into abnormal cells. AML ranks as the second most common leukemia in children, accounting for approximately four percent of all childhood and adolescent malignancies. Despite the use of intensive chemotherapy regimens, only around half of AML patients achieve long-term remission without relapse. Moreover, a significant proportion of children with AML require stem cell transplantation as a curative treatment. The limitations of current therapies, particularly the severe side effects associated with non-specific chemotherapy, highlight the urgent need for innovative and targeted approaches to leukemia treatment.
A research team led by Jan-Henning Klusmann from the Department of Pediatrics and Dirk Heckl from the Institute for Experimental Pediatric Hematology and Oncology at Goethe University Frankfurt has uncovered a potential Achilles heel of AML cells. Their study focused on a specific class of nucleic acids in leukemia cells known as noncoding RNAs. These molecules, similar to messenger RNAs (mRNAs), are produced through gene transcription. However, unlike mRNAs, which serve as blueprints for protein synthesis, noncoding RNAs play regulatory roles in cellular processes such as cell growth and division. Disruption of these regulatory pathways is a hallmark of cancer, making noncoding RNAs an attractive target for cancer therapy.
Driven by this rationale, the researchers sought to elucidate the role of noncoding RNAs in AML cells. They compiled a comprehensive inventory of these molecules in cancer cells derived from leukemic children and compared the obtained profile with that of healthy blood stem cells. This analysis revealed that AML cells exhibited differential expression of nearly 500 noncoding RNAs compared to healthy cells, suggesting their potential involvement in the cancer process. To validate this hypothesis, the researchers systematically silenced each of these noncoding RNAs by disrupting their corresponding genes in the genome. Intriguingly, the most striking effect was observed upon inactivation of the MYNRL15 gene. Leukemia cells lacking this gene lost their ability to proliferate indefinitely and ultimately perished. Unexpectedly, this effect was not attributed to the absence of noncoding RNAs but rather to the MYNRL15 gene itself, as Klusmann explains: “The regulatory function we observed is inherent to the MYNRL15 gene itself.” Further investigation revealed that disrupting the MYNRL15 gene altered the three-dimensional organization of the chromatin, the packaging material of DNA within cells. This disruption led to the silencing of genes essential for AML cell survival, providing a novel therapeutic strategy for combating leukemia.
Importantly, the inhibitory effect triggered by the modified MYNRL15 gene was evident across various AML cell lines, including those derived from both children and adults. Moreover, this effect extended to different subtypes of AML, including one prevalent in individuals with Down syndrome. “The fact that all the leukemias we studied were dependent on this gene locus highlights its critical importance,” concludes Klusmann. The researchers envision harnessing the cancer cells’ reliance on MYNRL15 to develop a specific gene therapy. “Our study represents the first systematic examination of noncoding RNAs and their corresponding genes in AML cells, and it has identified a promising target for future therapeutic development,” summarizes Klusmann.
KEY POINTS The discovery of MYNRL15 could lead to new and more effective treatments for leukemia that have fewer side effects. Gene therapy is a promising approach, and the researchers hope to begin clinical trials in the near future. Here are some of the key findings of the study: Leukemia cells are dependent on a gene called MYNRL15 for their survival. When MYNRL15 is turned off, the leukemia cells die off. MYNRL15 could be a promising target for gene therapy. This study is a significant step forward in the fight against leukemia. The discovery of MYNRL15 could lead to new and more effective treatments for this type of cancer that have fewer side effects.
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