Leukaemia stands as the most prevalent form of cancer afflicting children, necessitating an aggressive treatment approach primarily centred around intensive chemotherapy. Unfortunately, the efficacy of chemotherapy is hindered by severe side effects, attributed to its non-specific mode of action.
In response to this challenge, a team from the Department of Paediatrics and the Institute for Experimental Paediatric Haematology and Oncology at Goethe University Frankfurt has made a groundbreaking discovery that unveils a potential alternative therapy for leukaemia.Â
The researchers focused their investigation on acute myeloid leukaemia (AML), a subtype of leukaemia affecting blood cells in their early stages, including stem cells and precursor cells. AML accounts for approximately 4% of all malignant diseases in childhood and adolescence, and despite the application of intensive chemotherapy, only about half of affected children survive without relapse.
Furthermore, a considerable number of children rely on stem cell donation, emphasizing the critical need for more targeted and specific therapeutic approaches due to the severe side effects associated with non-specific chemotherapies. Led by Jan-Henning Klusmann and Dirk Heckl, the team identified a vulnerability in AML cells related to a specific site in the DNA.
Experimentally modifying the gene encoded at this site resulted in the death of cancer cells, marking it as a promising target for future alternative therapies. The researchers honed on a specific group of nucleic acids within leukemia cells known as noncoding RNAs, which, unlike regular messenger RNAs, do not translate into proteins but often assume regulatory functions in cellular processes such as growth and division.
Given the characteristic disruption of regulatory processes in cancer cells, noncoding RNAs became a compelling focus for the study. The team compiled an inventory of noncoding RNAs in AML cells, comparing them to healthy blood stem cells. The analysis revealed that AML cells differentially expressed nearly 500 noncoding RNAs, suggesting their crucial role in cancer cells.
To validate this, each of these RNA molecules was individually turned off, leading to a significant discovery related to the gene MYNRL15. When this gene was turned off, AML cells lost their ability to replicate indefinitely, ultimately causing their demise.Â
Interestingly, the researchers found that it wasn’t the absence of noncoding RNAs responsible for this effect, but rather the regulatory function of the MYNRL15 gene itself. Further investigations unveiled that the destruction of the MYNRL15 gene altered the spatial organization of chromatin, the three-dimensional structure of the genome, resulting in the deactivation of genes vital for the survival of AML cells.Â
The study’s significance lies in the universality of the inhibitory effect triggered by the modified MYNRL15 gene, observed across different AML cell lines, including those from both children and adults, and encompassing various subtypes of the disease. This includes a subtype prevalent in individuals with Down syndrome.Â
“The fact that all the leukaemia’s we studied were dependent on this gene locus tells us it must be important,” remarks Klusmann. The team is now optimistic that the dependence of cancer cells on MYNRL15 can be harnessed to develop a specific gene therapy, opening new and unforeseen possibilities in the fight against leukaemia.Â
In our study, we systematically examined noncoding RNAs and their genes in AML cells for the first time, and in the process, we identified a gene locus that constitutes a promising target for developing a therapy in the future,” says Klusmann. This groundbreaking research not only sheds light on the intricate mechanisms of leukaemia but also paves the way for innovative and targeted therapeutic strategies, offering hope for improved outcomes in the treatment of childhood leukaemia.Â
Journal Reference Â
Michelle Ng et al, Myeloid leukaemia vulnerabilities embedded in long noncoding RNA locus MYNRL15, iScience (2023). DOI: 10.1016/j.isci.2023.107844Â
