Leukemia, a type of blood cancer affecting people across all demographics, sees a staggering 320,000 new cases diagnosed in Europe each year. Among children, leukemia accounts for one-third of all cancer cases. The primary treatment for this devastating disease is chemotherapy. However, the exact cause remains largely unknown, and the molecular and cellular mechanisms driving leukemia are still shrouded in mystery. Addressing this challenge represents a significant breakthrough in the field of oncology.
Messenger RNA (mRNA) has garnered attention recently due to its role in COVID-19 vaccinations. In a groundbreaking article published in Molecular Cell, researchers from the Université libre de Bruxelles (ULB) and the Bordet Institute at Brussels University Hospital (Hôpital universitaire de Bruxelles—H.U.B.) have unveiled a novel avenue of research: harnessing the complex alphabet of mRNA, known as RNA epigenetics, to develop innovative anti-cancer therapies.
Similar to DNA, RNA consists of four well-known letters (A, U, G, C), but it also includes additional letters. One such letter is m5C, or methylation of messenger RNA, which plays a crucial role in gene regulation. Proteins, known as readers, bind to m5C to facilitate gene expression. However, the specific details of these m5C readers and their involvement in cancer remain poorly understood.
The research led by Prof. François Fuks, Director of the Laboratory of Cancer Epigenetics at ULB Faculty of Medicine and the Bordet Institute H.U.B., and Director of the ULB Cancer Research Center (U-CRC), has successfully identified a new RNA reader called SRSF2. This discovery sheds light on the critical role of the SRSF2 protein in leukemia development for the first time.
The SRSF2 gene is one of the most commonly mutated genes in leukemia cases, affecting up to 50% of certain leukemia types. The researchers have demonstrated that the SRSF2 protein recognizes the m5C modification in RNA. Additionally, they have identified an unexpected molecular mechanism that can lead to leukemia: mutations in the SRSF2 gene impair its ability to read m5C in RNA, consequently inhibiting its function in regulating messenger RNA.
Further analysis of nearly 700 leukemia patient samples led by Prof. François Fuks and his team revealed a new subgroup of patients with particularly poor survival outcomes due to the reduced m5C reading ability of SRSF2.
These groundbreaking discoveries, in conjunction with the expanding knowledge base surrounding the RNA alphabet, have been published in the journal Molecular Cell. They not only provide new insights into the etiology of leukemia but also open the door to a new paradigm in leukemia diagnosis and treatment based on RNA epigenetics.
This breakthrough research could enable specific diagnoses of patients with a grim prognosis, whose SRSF2 m5C reader function is compromised. Moreover, it paves the way for a novel therapeutic approach to leukemia by developing an inhibitor that can restore SRSF2’s ability to correctly read m5C. This reading ability is impaired in patients with the SRSF2 mutation.
Unleashing the potential of mRNA and understanding the complex alphabet of RNA has the power to revolutionize leukemia treatment. As the foundation of knowledge in this field continues to grow, these findings mark a significant step forward in the fight against this devastating disease.