A research team at Yale Cancer Center have discovered new consequences of specific gene mutations linked to the development of both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
The results were published in Molecular Cell on March 17, 2022.
In this new study, researchers have been able to show that mutations in the splicing factor U2AF1 makes cancer cells better at responding to and surviving stress.
Splicing factor mutations in cancer patients
RNA splicing is a fundamental process in our bodies. The genetic code is stored as DNA, but must be transcribed from DNA to RNA molecules for cell creation to occur. During RNA splicing, RNA molecules are cut, and select pieces are then reconnected by splicing factors. One of these factors is U2AF1. Mutations in splicing factors, e.g. in the U2AF1, can increase the risk of errors occuring during the process.
Roughly 50% of patients diagnosed with MDS and 10% of patients diagnosed with AML have splicing factor mutations that impairs blood cell production and leads to malignancy. Both AML and MDS starts in the bone marrow and is mostly diagnosed in older patients.
Splicing factor mutations are especially common in patients with MDS and AML, but have also been reported at an increased levels in studies regarding certain other forms of cancer.
Mutations in U2AF1
In the Yale Cancer Center study, researchers were able to show that U2AF1 mutations altered RNA binding, splicing and turnover of numerous RNAs, and that it enhanced the formation of stress granules.
Stress granules are condensates of RNAs and proteins, and they mediate the cells adaptation to stress.
“This discovery was possible by developing new experimental and analytic methods integrating big data. The mechanism of enhanced stress granule formation was not easy to detect, because it’s not caused by a single large change to one RNA molecule, but by the sum of many small changes to hundreds of RNA molecules,” said Toma Tebaldi, PhD, now Assistant Professor at the University of Trento, Adjunct Assistant Professor at Yale School of Medicine, and co-senior author on the paper.
Having a superior response to stress may (at least partly) explain why certain cancerous mutant cells have a clonal advantage in the body. Hopefully, understanding this process better will help scientists develop new ways to prevent and treat MDS and AML where U2AF1 mutations are involved.
“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,” said Stephanie Halene, MD, PhD, Chief of Hematology at Yale Cancer Center.
Biancon, G., et al. (2022) Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Molecular Cell.
Published in Molecular Cell on March 17, 2022
- Giulia Biancon, PhD, Postdoctoral Associate in the Halene Laboratory at Yale Cancer Center
- Poorval Joshi
- Joshua T. Zimmer
- Torben Hunck
- Yimeng Gao
- Mark D. Lessard
- Edward Courchaine
- Andrew E.S. Barentine
- Martin Machyna
- Valentina Botti
- Ashley Qin
- Rana Gbyli
- Amisha Patel
- Yuanbin Song
- Lea Kiefer
- Gabriella Viero
- Nils Neuenkirchen
- Haifan Lin
- Joerg Bewersdorf
- Matthew D. Simon
- Karla M. Neugebauer
- Toma Tebaldi
- Stephanie Halene
Funding was provided in part by:
Yale Cancer Center
Edward P. Evans Foundation
The National Institutes of Health
The State of Connecticut under the Regenerative Medicine Research Fund
The Yale Cooperative Center of Excellence in Hematology (YCCEH)