Disparate leukemia mutations converge on nuclear phase-separated condensates.

ABSTRACT: During cancer development, mutations promote changes in gene expression that cause transformation. Leukemia associated with aberrant HOXA expression is driven by translocations of nucleoporin genes or KMT2A as well as mutations in NPM1. The mechanistic convergence of these disparate mutations remains elusive. Here, we demonstrate that mutant nucleophosmin 1 (NPM1c) forms nuclear condensates in human cell lines, mouse models, and primary patient samples. We show NPM1c phase separation is necessary and sufficient to recruit NUP98 and KMT2A to condensates. Through extensive mutagenesis and pharmacological destabilization of phase separation, we find that NPM1c condensates are necessary for regulating gene expression, promoting in vivo leukemic expansion, and maintaining the undifferentiated l

SUBMITTER: Datar GK 

PROVIDER: S-EPMC12773745 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature