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Paediatric Oncology: Scientists Discover New Achilles Heel of Leukaemia Cells

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The term “leukaemia” encompasses various forms of blood cancer, including acute myeloid leukemia (AML). In AML, blood cells in the early stages – the stem cells and the precursor cells that develop out of them – degenerate. AML is the second most common leukaemia in children, accounting for around 4% of all malignant diseases in childhood and adolescence. Despite intensive chemotherapy, only around half of those affected survive without relapsing. About one third of children are dependent on a stem cell donation. Since non-specific chemotherapies have severe side effects, there is an urgent need to find new and specific therapy approaches.

A 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 now discovered an unusual “Achilles heel” in AML cells. For their study, published in iScience, they looked at a specific group of nucleic acids in leukaemia cells: non-coding RNAs. Just like regular messenger RNAs (mRNAs), these are produced through gene transcription.

However, unlike mRNAs, non-coding RNAs are not translated into proteins but instead often assume regulatory functions, for example, in cell growth and cell division. A typical characteristic of cancer cells is a massive disruption of regulatory processes. This makes non-coding RNAs an interesting starting point in the fight against cancer.

Against this background, the researchers led by Klusmann and Heckl wanted to know more about the role of non-coding RNAs in AML cells. For this purpose, they compiled a kind of inventory of these molecules in cancer cells taken from sick children and compared the resulting pattern with that of healthy blood stem cells. AML cells differentially expressed almost 500 non-coding RNAs in comparison to healthy cells – an indication that they could perform an important function in cancer cells.

To validate this, the researchers turned off every single one of these RNA molecules by preventing the coding gene in the genome from being read. The most distinct effect they found was for the gene MYNRL15. Cancer cells in which this gene was turned off lost their ability to replicate indefinitely and died off.

Surprisingly, however, it was not the absence of non-coding RNAs that was responsible for this effect, as Klusmann commented: “The regulatory function we observed is due to the MYNRL15 gene itself.” The team was able to show that destroying the gene altered the spatial organisation of the chromatin, i.e. the three-dimensional structure of the genome. “This led to the deactivation of genes that AML cells need for survival,” said Klusmann. This offers a new and unforeseen possibility for fighting leukaemia.

What is significant against this background is the fact that the inhibitory effect triggered by the modified MYNRL15 gene could be observed in different AML cell lines. These cells originated both from children as well as adults and included various subtypes of the disease – among them, one common in people with Down syndrome.

“The fact that all the leukaemias we studied were dependent on this gene locus tells us it must be important,” concluded Klusmann. The researchers now hope that the cancer cells’ dependence on MYNRL15 can be used to develop a specific gene therapy. “In our study, we systematically examined non-coding 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.”

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