Scientists from Lund University’s Faculty of Medicine have discovered a novel mechanism connecting ribonucleic acid (RNA) metabolism to the development of leukemia in patients with myelodysplastic syndrome (MDS). They describe what causes hematopoietic stem cells to attain malignant characteristics in cancer in a study published in the journal Molecular Cell.
RNA splicing is a key regulator of gene expression, defining cellular identity during development, and is commonly altered in human cancers. This process is mediated by the spliceosome, a complex molecular machinery that allows the production of multiple and functionally distinct proteins from a single gene.
Dr Cristian Bellodi’s group discovered recently a hardwired genetic control mechanism modifying individual spliceosomal components known as splicing factors in cells harboring oncogenic lesions widespread in human cancers.
This study focused on core splicing proteins, such as SF3B1, which are frequently mutated in cancers. Mutations in splicing factors are especially common in MDS, a group of heterogeneous hematological disorders characterized by damaged blood stem cells and an increased risk of leukemia development.
“Accumulating evidence is highlighting a role for aberrant splicing in cancer even in the absence of splicing factors mutations. However, little is known about the contribution of the non-mutated splicing factors in tumor evolution,” the investigators elaborated.
The researchers began by looking into how non-mutated SF3B1, a key spliceosome component, contributes to MDS. Maciej Cieśla and colleagues found dynamic regulation of SF3B1 levels during the malignant transformation from MDS to leukemia in collaboration with Prof. Eva Hellström-group Lindberg’s at the Karolinska Institute.
Strikingly, we found that SF3B1 protein accumulates in MDS patients to ensure genome integrity via splicing regulation. Blocking this mechanism drastically accelerates progression to aggressive leukemia.”
Maciej Cieśla, Study First Author and Postdoctoral Fellow, RNA and Stem Cell Biology Group, Lund University Stem Cell Center
Maciej Cieśla is now working as a group leader at IMOL in Poland.
The researchers then looked into the molecular factors that control SF3B1 production during the transition to leukemia. These investigations led to the ground-breaking discovery that SF3B1 synthesis is dependent on a single RNA chemical modification mark known as N6-methyladenosine, m6A, that is deposited on its messenger RNA.
“We found that the presence of m6A RNA modification provides a “stop signal” that regulates SF3B1 production, a critical event that impacts accumulation of DNA damage in leukemic cells,” explains Maciej Cieśla.
Our results revealing a new critical connection between RNA metabolism and genome integrity in leukemic stem cells, provide important insights into the complex underlying mechanisms fueling cancer development in MDS patients. Our findings are particularly timely, as increasing evidence indicates that RNA modification and splicing alterations represent new therapeutic vulnerabilities for treating hematological and solid cancer patients.”
Cristian Bellodi, Associate Professor, Division of Molecular Hematology and Lund Stem Cell Center, Lund University
Cieśla, M., et al. (2023). m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis. Molecular Cell. doi.org/10.1016/j.molcel.2023.02.024.