Abstract / Summary
Abstract 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.