10 February 2020

Researchers have revealed how a common mutation sets off a chain of biological events that lead to many forms of leukaemia.

RNA splicing is an essential process in the cell, where messages encrypted into the DNA code are chopped up and glued back together. This process creates new templates for making proteins in the cell.

Errors in RNA splicing can result in poorly formed proteins that cannot do their job. One of the checks in place to prevent this from happening is called Nonsense-mediated mRNA decay, or NMD. This normally serves as ‘quality control’, destroying messages that contain mistakes before a broken protein is made. However, USA biologists have now found that NMD is excessively active in leukaemia.

The team leading the study was made up of scientists from Cold Spring Harbor Laboratory and Memorial Sloan Kettering Cancer Center in New York, and Fred Hutchinson Cancer Research Center in Seattle. They set out to investigate the role of an RNA splicing gene called SRSF2, mutations in which are very common in leukaemia. The scientists found that when SRSF2 is mutated, NMD destroys many more messages than normal, including some that are important for healthy blood cell production.

The result of excessively active NMD is fewer healthy blood cells and more sickly or immature cells, which are hallmarks of blood cancer.

[https://www.youtube.com/watch?v=7OoY0tbi8TU]

“RNA splicing factor mutations are seen in virtually all forms of leukaemia, both chronic as well as acute myeloid leukaemias and also even chronic lymphocytic leukaemia,” said Dr Omar Abdel-Wahab, one of the research team from Memorial Sloan Kettering.

Although it is already known that other cancers manipulate NMD into protecting solid tumours, the researchers say this new discovery, published in the journal Genes and Development, is the first evidence of NMD contributing to blood cancers.

The research team tested antisense oligonucleotide (ASO) therapy to stop the mutated SRSF2 gene from enhancing NMD. The technique has been previously used to combat other diseases resulting from defective RNA splicing. The next step will be to test ASOs in animals.

 

Source:

Rahman MA, Lin KT, Bradley RK, Abdel-Wahab O, Krainer AR (2020) “Recurrent SRSF2 mutations in MDS affect both splicing and NMD”, Genes & Development, doi:  10.1101/gad.332270.119