IRIC - Institute for Research in Immunology and Cancer

Published on April 4, 2023

RNAs, messengers of genetic information, are sometimes altered in cancer cells in a way that leads to changes in the original directions sent from the DNA. RNAs are initially produced from the DNA in an immature form and need to undergo structural and chemical changes in order to be ready for their conversion into protein. One of these changes is called splicing and involves cutting noncoding segments within the RNA, and in case of alternative splicing different noncoding and coding segments leading to variety of altered RNA messages, and ultimately changes in levels and/or functions of final protein products.

The team of Professor Katherine Borden, Director of the Structure and Function of the Cell Nucleus Research Unit at IRIC, set out to understand how alternative splicing was hijacked in certain patients with Acute Myeloid Leukemia (AML) who do not harbour the DNA mutations usually associated with splicing dysregulation. The study of laboratory models and samples from leukemia patients has made it possible to discover that the splicing of thousands of RNAs could be altered in an unsuspected way by the oncogenic protein eIF4E, conferring cancerous properties to the cells. Published in The EMBO Journal, the work was jointly led by postdocs Mehdi Ghram and Gavin Morris, along with research associate Biljana Culjkovic-Kraljacic.

Reprogramming of splicing in a mutation-independent way

Dysregulation of RNA splicing is generally associated with the presence of mutations within components of the cellular splicing machine known as the spliceosome. Here, the dysregulation of eIF4E increased the production of certain key splicing proteins thereby generating an altered splicing landscape within the cell in the absence of mutations. eIF4E drove increased levels of these splicing factors through a combination of increasing the nuclear export of their corresponding RNAs to the cytoplasm and in some cases by stimulating their conversion into protein in a process known as translation. Moreover, it was observed that eIF4E physically associates with the spliceosome and with RNA targets of splicing, suggesting eIF4E could also play direct role in the splicing process for at least some RNAs.

A paradigm shift for splicing regulation that could have clinical significance

The discovery of this widescale reprogramming of splicing sheds light on a completely new way for eIF4E to contribute to cancers. By acting simultaneously on several actors of the splicing machinery, eIF4E induces a much wider range of alterations to the splicing programme than individual mutations, increasing its oncogenic potential. The work of the Borden laboratory therefore provides a better understanding of the mechanisms underlying the dysregulation of splicing in the absence of mutations. These results could allow the use of splicing inhibitors to be extended to AML patients who do not harbor mutations in the splicing machinery.

Cited study :

Mehdi Ghram, Gavin Morris, Biljana Culjkovic-Kraljacic, Jean-Clement Mars, Patrick Gendron, Lucy Skrabanek, Maria Victoria Revuelta, Leandro Cerchietti, Monica L Guzman, Katherine L B Borden. The eukaryotic translation initiation factor eIF4E reprograms alternative splicing. The EMBO Journal. 2023; e110496. https://doi.org/10.15252/embj.2021110496