Abnormal nucleoli architecture and aggregate formation in nucleophosmin mutated acute myeloid leukaemia

TL;DR

This study shows that NPM1 mutations in AML cause abnormal nucleoli structure and function, and lead to protein aggregation, offering new insights into potential treatments.

Contribution

The study reveals that NPM1 mutations cause reversible nucleolar abnormalities and identify novel protein aggregates in AML.

Findings

NPM1 mutations disrupt nucleoli architecture and increase RNA polymerase I activity.

Perinucleolar chromatin organization is altered in NPM1-mutated cells.

NPM1 mutated protein forms distinct aggregates, a previously uncharacterized phenomenon.

Abstract

Mutations in the nucleophosmin (NPM1) gene represent the most common genetic alteration in acute myeloid leukaemia (AML) and result in mis-localisation of the mutated protein from a predominantly nucleolar localisation to a predominantly cytoplasmic distribution. Here, we use high resolution imaging to demonstrate that NPM1 is crucial for maintaining normal nucleoli architecture and specifically the integrity of the enigmatic nucleoli rim, the least understood nucleolar compartment. We demonstrate that cell lines and primary cells with NPM1 mutations from individuals with AML have aberrant nucleoli architecture; intriguingly this abnormal nucleolar phenotype is reversible. Using a surrogate for rRNA synthesis, we show that the aberrant phenotype is associated with differences in nucleolar function; specifically, activity of RNA polymerase I is increased in NPM1 mutated cells. Perinucleolar chromatin organisation is also markedly different in NPM1 mutant cells. Finally, we report the novel finding that NPM1 mutated protein forms distinct aggregates and characterise these for the first time. This work reveals how nucleolar organisation contributes to the molecular mechanisms underpinning NPM1-driven AML, revealing novel therapeutic vulnerabilities.

Highlighted Article:
Nucleophosmin (NPM1) mutated acute myeloid leukaemia cells have aberrant nucleoli architecture and function along with perinucleolar heterochromatin reorganisation. NPM1 mutated protein also forms distinct aggregates.

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