Discoveries about a fundamental protein may open the way for new treatments for leukaemia, researchers have reported.
Exportin-1, a protein found in all living organisms, export molecules like proteins and RNA out of the nucleus. It also plays a role in gene transcription, according to researchers at Northwestern University, Illinois, USA.
The protein is often over-produced in leukaemia and other cancers, the researchers say, and is already a target of some treatments.
The findings, reported in Molecular Cell, come from fundamental research in yeast into the activity of the Crm1 protein (the yeast equivalent of Exportin-1), examining it through genome-wide mapping, biochemistry and single molecule tracking.
The team show that Crm1 in yeast physically links chromatin (DNA packaged up with proteins) to nuclear pore complexes, the holes in the nucleus which allow molecules to enter and exit. By moving chromatin towards the nuclear pore complexes, Crm1 increases the activity of hundreds of genes.
The researchers say their discoveries relating to Crm1 in yeast suggest that Exportin-1 in humans could promote cancer development by enhancing the expression of genes responsible for cell division. They believe it might be possible to inhibit this process – although they recognise the theory is in very early stages.
Researcher Professor Jason Brickner said: “Because Exportin-1 is often overexpressed in cancers and leukaemia, this work also raises the possibility that this newly discovered function is important in promoting cancer growth.
“The work provides a molecular explanation for a phenomenon I discovered 20 years ago — the movement of genes to the nuclear periphery when they are turned on.”
Fellow researcher Tiffany Ge said: “Exportin-1 is overexpressed in many leukaemias and cancers. Because it binds to the genome, it may alter transcription to promote oncogenesis.”
“Inhibitors of Exportin-1 are given to patients who fail to respond to first- or second-line chemotherapies. But these therapies are very toxic and have many side effects because they block all nuclear export, which is an essential function of cells.”
Source:
Ge T, Brickner DG, Zehr K, VanBelzen DJ, Zhang W, Caffalette C, Moeller GC, Ungerleider S, Marcou N, Jacob A, Nguyen VQ, Chait B, Rout MP, Brickner JH. (2025) “Exportin-1 functions as an adaptor for transcription factor-mediated docking of chromatin at the nuclear pore complex.” Molecular Cell, 20 March 2025, doi: 10.1016/j.molcel.2025.02.013.
Link: https://www.cell.com/molecular-cell/fulltext/S1097-2765(25)00144-3
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