In Belgium, around 1,300 new cases of leukemia are diagnosed every year, a type of blood cancer that affects the entire population. In children, leukemia accounts for 1/3 of all cancer diagnoses. Chemotherapy is the main treatment for leukemia. Often, the exact cause cannot be determined, and the molecular and cellular mechanisms responsible for leukemia remain largely mysterious. Discovering new ways of detecting and treating leukemia is therefore a major challenge in oncology.
Messenger RNA has received a lot of media coverage in recent months, thanks to vaccines against COVID-19. In a publication in Molecular Cell, researchers from the Université libre de Bruxelles (ULB) and Institut Bordet, Hôpital universitaire de Bruxelles (H.U.B.) open up another, equally innovative avenue of research: novel anti-cancer therapies thanks to the complex alphabet of messenger RNA (or RNA epigenetics).
As with DNA, in addition to the 4 well-known letters (A, U, G, C), additional letters chemically dress up RNA. This is the case for the letter m5C, or messenger RNA methylation, which plays an essential role in gene regulation, thanks to the reading of m5C by proteins that bind to it, known as "readers". These m5C readers are still poorly described, and their role in cancer is unknown.
Recent work by the team of Prof. François Fuks - Director of the Cancer Epigenetics Laboratory, ULB Faculty of Medicine and Institut Bordet H.U.B. and Director of the ULB Cancer Research Center (U-CRC), Université libre de Bruxelles - has identified a new RNA reader, SRSF2, and lifted the veil for the first time on the key role played by the SRSF2 protein in the development of leukemia.
up to 50% in certain types of leukemia. The researchers demonstrated that the SRSF2 protein reads the m5C modification in RNA; they also uncovered a hitherto unsuspected molecular mechanism leading to leukemia: mutation of SRSF2 impairs its ability to read m5C on RNA, thereby impairing its function in regulating messenger RNAs. In addition, by analyzing nearly 700 samples from leukemia patients, Prof. François Fuks and his colleagues were able to identify a new group of patients whose survival is particularly hampered by SRSF2’s impaired ability to read m5C.
This work, part of the burgeoning era of the RNA alphabet, is published this December 7, 2023 in the journal Molecular Cell.
These discoveries should not only open up a new chapter in our understanding of how leukemia develops, they should also point us towards a new paradigm for the diagnosis and treatment of leukemia, based on RNA epigenetics. In concrete terms, the findings could lead to the specific diagnosis of patients with a poor vital prognosis, whose SRSF2 "m5C reader" function is affected. In addition, a new therapeutic approach to leukemia could be envisaged by developing an inhibitor that would restore the correct reading of m5C by SRSF2, this reading being impaired in patients carrying the SRSF2 mutation.
The work is supported by the F.N.R.S, Télévie, Welbio, the Fondation contre le Cancer, an ARC, the ULB Foundation and Wallonia.