Common leukemia mutation derails protein positioning during cell division, study reveals
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Experts from the University of Nottingham have discovered how a common genetic mutation disrupts the positioning of a key protein during cell division, revealing a new mechanism behind acute myeloid leukemia and a potential avenue for future treatment.
Acute myeloid leukemia (AML) is an aggressive blood cancer that disrupts the production of healthy blood cells. Around one-third of patients carry a mutation in a gene called NPM1, which causes its protein to accumulate in the wrong part of the cell and plays a key role in driving the disease.
Until now, research has largely focused on how the mutated protein moves between the cell's nucleus and the surrounding cytoplasm. But a new study, led by Dr. Daniel Booth and Dr. Claire Seedhouse at the University of Nottingham's School of Medicine, reveals that what happens during cell division itself is also critical.
Published in Nature Communications, the findings uncover a previously unknown mechanism that helps explain how the mutation disrupts the normal organization of proteins inside leukemia cells.
"For many years, researchers have focused on how this mutated protein is transported around the cell. What we've discovered is that something important happens during cell division itself. The surface of chromosomes acts like a temporary docking station, helping proteins find their way back to the right place after a cell divides. In leukemia cells, this process doesn't work properly," said Booth.
A disrupted docking site on chromosomes
At the heart of the discovery is the mitotic chromosome periphery, a protective layer surrounding chromosomes during cell division that has received relatively little scientific attention.
Using advanced microscopy, genetic engineering and protein-mapping techniques, the researchers found that healthy NPM1 attaches to this layer during cell division, helping it return to its correct location afterward.
Mutated NPM1 behaves differently. It fails to attach properly to chromosomes, instead forming abnormal clusters or dispersing throughout the cell. The mutant protein also interferes with healthy NPM1, further disrupting its ability to return to the right place.
Together, these findings reveal two previously unrecognized ways in which cell division contributes to the abnormal positioning of NPM1 in leukemia.
Ki-67 helps restore protein positioning
The researchers also found that this process could be partially restored in laboratory experiments.
By increasing levels of Ki-67, a protein that helps organize the chromosome periphery, the team created a thicker layer around chromosomes. This improved the attachment of mutant NPM1 to chromosomes in laboratory-grown leukemia cells, helping restore its correct positioning and normal cellular organization.
The finding is particularly intriguing because Ki-67 is widely used as a marker of cell proliferation and is generally associated with more aggressive cancers. However, analysis of publicly available patient data revealed a more complex picture: Among patients with this particular form of AML, higher Ki-67 levels showed an unexpected trend toward better survival.
This observation highlights the need for further research to understand the relationship between Ki-67, chromosome organization and patient outcomes.
"What's particularly exciting is that we've shown we can improve this process experimentally. It's early-stage research, but it reveals a completely new way of thinking about how this form of leukemia develops and, potentially, how we might treat it," said Seedhouse.
Patient samples support a potential treatment avenue
The researchers also confirmed that the newly identified mechanism occurs in samples taken directly from AML patients, strengthening the clinical relevance of the findings.
The discovery challenges the longstanding view that abnormal movement of NPM1 between the nucleus and cytoplasm is the principal explanation for its mislocalization. Instead, it identifies interactions between proteins and chromosomes during cell division as another important contributor.
Although further research is needed before the findings can inform clinical treatments, the study provides early evidence that manipulating the chromosome periphery could help restore normal protein positioning and potentially complement existing therapies.
The implications may also extend beyond leukemia. Because the abnormal positioning of proteins is involved in a range of diseases, understanding how cells organize proteins during division could open new avenues for research into other conditions.
By uncovering an unexpected link between chromosome biology and blood cancer, the University of Nottingham team has revealed a new direction for understanding, and potentially treating, diseases driven by misplaced proteins.
Publication details
Martin Grundy et al., Ki-67, the chromosome periphery and de-compartmentalisation each contribute to nucleophosmin mislocalisation in acute myeloid leukaemia, Nature Communications (2026). DOI: 10.1038/s41467-026-78560-3
Journal information: Nature Communications
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Sadie Harley
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