16 June 2022

A Spanish study has revealed insights into how chemical modifications to RNA molecules might have a role in reversing the spread of leukaemia.

Researchers have discovered how cancer cells switch to other types of cells, and how they alter the chemical modifications on their RNA molecules in the process. The team identified the key role of a protein called METTL3, which is already a target for cancer drugs in development.

Messenger RNAs (mRNAs) are genetic molecules onto which the DNA code is written in order to manufacture proteins in the cell. Modifications on the mRNAs called methylated adenosine (m6A) can alter how much of a protein is made.

Researchers at the University of Barcelona studied first of all how leukaemia cells changed type to avoid treatment – such as acute lymphoblastic leukaemia cells becoming myeloid cells like macrophages.

They then developed a lab-based model in which leukaemia cells could be converted to macrophages at will. They showed that during this process, there is a massive reorganisation in the m6A modifications on mRNAs.

They then turned to METTL3 – a protein which ‘writes’ the m6A changes onto mRNAs. Blocking this protein, either by preventing it from being made or with drugs – preventing cells from switching. The research was published in the journal Leukemia.

Study leader Professor Manel Esteller, from Josep Carreras Leukaemia Research Institute, said: “We know that one strategy that human tumours have to dodge the effectiveness of drugs is to change their appearance, becoming another similar cancer but insensitive to the drug used. For example, leukaemias of the lymphoid lineage are switched to the myeloid strain to escape treatment.”

Speaking about how METTL3 appears to be coordinating this process, Esteller says: “the first preclinical drugs against this target have already been developed in experimental models of malignant blood diseases, so we provide another reason why these novel drugs could be useful in cancer therapies, particularly in the case of leukaemias and lymphomas.”

Source: Bueno-Costa A, Piñeyro D, García-Prieto CA, Ortiz-Barahona V, Martinez-Verbo L, Webster NA, Andrews B, Kol N, Avrahami C, Moshitch-Moshkovitz S, Rechavi G, Esteller M. (2022) “Remodelling of the m6A RNA landscape in the conversion of acute lymphoblastic leukemia cells to macrophages.” Leukemia, doi: 10.1038/s41375-022-01621-1

Link: https://www.nature.com/articles/s41375-022-01621-1

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