A novel mechanism that links the metabolism of ribonucleic acids (RNA) to the development of leukaemia in myelodysplastic syndrome (MDS) patients has been identified by researchers in Sweden.
RNA splicing plays a crucial role in gene expression regulation, and shapes cellular identity during development. The process of RNA splicing is mediated by the spliceosome, which enables the production of multiple and functionally distinct proteins from single genes.
Recent work by Dr Cristian Bellodi from Lund University Faculty of Medicine showed how the proteins of the spliceosome, including one called SF3B1, are frequently mutated in various cancers.
Splicing factor mutations are particularly prevalent in MDS, a group of conditions which have a high risk of progressing into leukaemia. There is growing evidence there is 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 leukaemia evolution.
For this study, the team led by Dr Bellodi investigated how the levels of non-mutated SF3B1, one of the core spliceosome components, contribute to the MDS disease. The team found that the amount of SF3B1 present in the cells changes during the malignant transformation from MDS to leukaemia.
They discovered that SF3B1 protein accumulates in MDS patients to ensure genome integrity via splicing regulation, and slows down progression to leukaemia. Reducing levels of SF3B1 drastically accelerates progression to aggressive leukaemia.
They went on to examine the how SF3B1 production is controlled during the transition to leukaemia. This led to the breakthrough discovery that SF3B1 synthesis depends on N6-methyladenosine (m6A) deposited on its messenger RNA. The m6A modification provides a “stop signal” that prevents the production of SF3B1, which subsequently leads to genome instability and ultimately progression to leukaemia.
Dr Bellodi said: “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 fuelling 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 haematological and solid cancer patients.”
Source:
Cieśla M, Ngoc PCT, Muthukumar S, Todisco G, Madej M, Fritz H, Dimitriou M, Incarnato D, Hellström-Lindberg E, Bellodi C. (2023) “m6A-driven SF3B1 translation control steers splicing to direct genome integrity and leukemogenesis.” Molecular Cell, doi: 10.1016/j.molcel.2023.02.024.
Link: https://www.cell.com/molecular-cell/fulltext/S1097-2765(23)00151-X
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