Ki-67, the chromosome periphery and de-compartmentalisation each contribute to nucleophosmin mislocalisation in acute myeloid leukaemia

The mitotic chromosome periphery (MCP) is an important chromosome compartment but links to disease remains elusive. Here we define the mitosis-specific, Ki-67 interactome, identifying additional MCP components and revealing that MCP genes are commonly mutated in cancer, including nucleophosmin (NPM1). Acute myeloid leukaemia (AML)-specific NPM1 mutations (NPM1c + ), result in protein mislocalisation (nucleolus to cytoplasm). We demonstrate that NPM1c+ fails to adequately bind to the MCP, instead forming aggregates during mitosis. We also report that, de-compartmentalisation at mitotic onset allows formation of NPM1wt/c+ multimers. These mislocalisation mechanisms contribute to a significant hinderance of NPM1 re-entry into daughter cell nucleoli. Enhancing MCP loading capacity via Ki-67 overexpression resulted in increased MCP-bound NPM1c+ during mitosis and greater yield of nucleolar NPM1c + . Ki-67 expression demonstrated a significant interaction with NPM1 mutation status on AML patient overall survival, whereby higher Ki-67 was associated with increased hazard in NPM1wt but reduced hazard in NPM1c+ patients. This work reveals mechanistic insight into AML and evidence that the MCP has untapped therapeutic potential.