Disparate Leukemia Mutations Converge on Nuclear Phase-Separated Condensates

Authors

• Gandhar K Datar
• Elmira Khabusheva
• Archish Anand
• Joshua Beale
• Marwa Sadek
• Chun-Wei Chen
• Evdokiia Potolitsyna
• Nayara Alcantara-Contessoto
• Guangyuan Liu
• Josephine De La Fuente
• Christina Dollinger
• Anna Guzman
• Alejandra Martell
• Katharina Wohlan
• Abhishek Maiti
• Nicholas J Short
• S Stephen Yi
• Vibeke Andresen
• Bjørn Tore Gjertsen
• Brunangelo Falini
• Rachel E Rau
• Lorenzo Brunetti
• Nidhi Sahni
• Margaret A Goodell
• Joshua A Riback

Language

English

Publication Date

12-11-2025

Journal

Cell

DOI

10.1016/j.cell.2025.10.010

PMID

41192422

PMCID

PMC12773745

PubMedCentral® Posted Date

2-5-2026

PubMedCentral® Full Text Version

Author MSS

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 leukemic state. Finally, we show that nucleoporin and KMT2A fusion proteins form condensates that are biophysically indistinguishable from NPM1c condensates. Together, these data define a new condensate that we term the coordinating body (C-body) and establish C-bodies as a therapeutic vulnerability in leukemia.

Keywords

Nucleophosmin, Humans, Animals, Nuclear Proteins, Nuclear Pore Complex Proteins, Mice, Myeloid-Lymphoid Leukemia Protein, Mutation, Leukemia, Histone-Lysine N-Methyltransferase, Cell Nucleus, Cell Line, Tumor

Published Open-Access

yes

Recommended Citation

Datar, Gandhar K; Khabusheva, Elmira; Anand, Archish; et al., "Disparate Leukemia Mutations Converge on Nuclear Phase-Separated Condensates" (2025). Faculty, Staff and Students Publications. 6517.
https://digitalcommons.library.tmc.edu/baylor_docs/6517