Two interacting faulty genes may play a key role in the development of acute myeloid leukaemia (AML) in some patients, British researchers have reported.
Both genes are currently the target of drugs under development. The researchers say that their latest study suggests that in the future, a combination of the two treatments could prove effective.
The scientists studied the DNA of samples donated by nearly 1,000 AML patients. They showed that the leukaemia cells in about 10% of patients carried faults in the SRSF2 gene and that about half of these also suffered damage to another gene, IDH2.
Both genes have previously been linked to the disease, but the researchers say mutations in the two genes occur together more often than would be expected by chance alone. They demonstrated in mice models that the two gene faults work together they cause “huge disruption” to RNA splicing, leading to leukaemia developing much faster.
They also showed that the protein INTS3 is disrupted and inactivated in these patients, connecting it to leukaemogenesis for the first time.
The study, published in Nature, involved researchers from the University of Manchester and Memorial Sloan Kettering Cancer Center, New York, USA.
Researcher Dr Daniel Wiseman, from Manchester, said: “There is a lot of excitement around precision medicines that target specific genetic mutations in cancer cells, but to make this a reality we need to better understand what these mutations do, and importantly how they work together in patients.
“Our research shows one of the first examples of how faults in two very different cancer genes cooperate together and bring about other, unpredicted consequences. This helps us better understand the complicated process by which healthy blood cells turn into leukaemia cells. It also suggests that sometimes the best way to kill cancer cells might be to target different genetic mutations in combination.”
Dr Alasdair Rankin, from the charity Bloodwise which helped fund the research, said: “Curing AML today is really difficult and needs treatments that are just too harsh for most patients. Blood cancer research is putting new precision medicines in the hands of doctors that allow kinder treatments for more people.
“We can turn this progress into cures for everyone with AML, but we need to understand how to use these new drugs in the right way in the right person - this important study shows us how we can get there.”
Source: Yoshimi, A., Lin, K.T., Wiseman, D.H., Rahman, M.A., Pastore, A., Wang, B., Lee, S.C., Micol, J.B., Zhang, X.J., de Botton, S., Penard-Lacronique, V., Stein, E.M., Cho, H., Miles, R.E., Inoue, D., Albrecht, T.R., Somervaille, T.C.P., Batta, K., Amaral, F., Simeoni, F., Wilks, D.P., Cargo, C., Intlekofer, A.M., Levine, R.L., Dvinge, H., Bradley, R.K., Wagner, E.J., Krainer, A.R., Abdel-Wahab, O. (2019) “Coordinated Alterations in RNA Splicing and Epigenetic Regulation Drive Leukaemogenesis”, Nature, doi: 10.1038/s41586-019-1618-0
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