01 April 2022

Scientists studying the role of specific mutations in myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) believe that they have identified a new mechanism for disease development.

In about half of patients diagnosed with MDS and 10% of AML patients, their cancer cells have mutations in ‘splicing factor’ genes, such as U2AF1 and SF3B1. RNA splicing is a mechanism which allows new proteins to be made from the same genetic template, allowing for diversity among cells in the body.

Mutations in the splicing factors which control RNA splicing lead to ineffective blood cell production and malignancy. A team led by Dr Stephanie Halene from Yale Cancer Center, New Haven, USA, set out to understand the mechanism of how these mutations might lead to cancer.

Writing in Molecular Cell, the research team found mutations in the splicing factor U2AF1 improve the ability of the cancer cells to respond to and survive stress. Mutations in U2AF1 alter RNA binding, splicing, and turnover of numerous RNAs.

This enhances the formation of stress granules, clumps of RNAs and proteins which protect the cell from stress. The team says this improved stress response may explain the growth advantage that mutant cells have over healthy cells, and the development of MDS or AML.

Lead study author Dr Giulia Biancon, postdoctoral associate in the Halene Laboratory at Yale Cancer Center, said: “The discovery that U2AF1 mutations enhance stress granule formation may open novel avenues to prevent or treat myelodysplastic syndromes and acute myeloid leukaemia.”

MDS are most common in patients over 70 years and are conditions that can occur when the blood-forming cells in the bone marrow become abnormal. AML also starts in the bone marrow and is most commonly diagnosed in older patients, but most often it quickly moves into the blood, as well.

Dr Stephanie Halene, chief of haematology at Yale Cancer Center, said: “Our finding that mutations in U2AF1 alter stress granule formation via aberrant RNA binding and splicing leads us to believe that this mechanism could underly the pathogenicity of the other common splicing factor mutations in MDS.

“If this is a more universal mechanism we could harness it for novel treatments for these diseases.”

Source: Biancon G, Joshi P, Zimmer JT, Hunck T, Gao Y, Lessard MD, Courchaine E, Barentine AES, Machyna M, Botti V, Qin A, Gbyli R, Patel A, Song Y, Kiefer L, Viero G, Neuenkirchen N, Lin H, Bewersdorf J, Simon MD, Neugebauer KM, Tebaldi T, Halene S. (2022) “Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies.” Molecular Cell, doi: 10.1016/j.molcel.2022.02.025

Link: https://www.cell.com/molecular-cell/fulltext/S1097-2765(22)00163-0

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