The exact cause and the molecular and cellular mechanisms responsible for leukemia have not been fully understood. Discovering new detection methods and new treatments to eradicate leukemia is therefore a major challenge in oncology. New research by scientists from the Université libre de Bruxelles (ULB) and the Bordet Institute, Brussels University Hospital (Hôpital universitaire de Bruxelles—H.U.B.) explores novel anticancer therapies using the complex alphabet of messenger RNA (or RNA epigenetics).

Their findings are published in Molecular Cell in an article titled, “SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.”

“A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear,” the researchers wrote. “Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis.”

m5C, or methylation of messenger RNA, plays an essential role in gene regulation through the reading of m5C by proteins that bind to it, called “readers.” These m5C readers have still not been described in detail and their role in cancer is unknown.

The recent work of the team led by François Fuks, PhD, director of the Laboratory of Cancer Epigenetics, ULB Faculty of Medicine and Bordet Institute 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 its role in the development of leukemia.

The SRSF2 gene is one of the most frequently mutated genes in leukemia cases: up to 50% in certain types of leukemia. The researchers demonstrated that the SRSF2 protein reads the m5C modification in RNA; they also highlighted a previously unsuspected molecular mechanism that can lead to leukemia: the mutation of SRSF2 alters its ability to read m5C in RNA, which inhibits its function of regulating messenger RNA.

After analyzing nearly 700 samples taken from leukemia patients, Fuks and his colleagues were able to identify a new group of patients whose chances of survival are particularly low due to the reduced ability of SRSF2 to read m5C.

Their findings not only open a new door to understanding why leukemia appears, but it may lead to new therapeutic strategies and studies based on the epigenetics of RNA.

“Although the path from mutation to disease remains to be fully elucidated, our work suggests that impairment of the SRSF2 m5C reader function can contribute to leukemia progression,” concluded the scientists. “Overall, our data identify unrecognized mechanistic crosstalk between RNA modifications and an important mutation-dependent factor.”

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