美国贝勒医学院Joshua A. Riback小组的一项最新研究发现了不同的白血病突变聚集在核相分离凝聚体上。该研究于2025年11月4日发表于国际一流学术期刊《细胞》杂志上。

该课题组人员证明突变型核磷蛋白1（NPM1c）在人类细胞系、小鼠模型和原发性患者样本中形成核凝聚物。研究团队发现NPM1c相分离对于将NUP98和KMT2A引入冷凝物是必要和充分的。通过广泛的诱变和相分离的药理学不稳定，课题组发现NPM1c凝聚物是调节基因表达、促进体内白血病扩张和维持未分化白血病状态所必需的。最后，小组发现核孔蛋白和KMT2A离子蛋白形成的凝聚体在生物物理上与NPM1c凝聚体无法区分。总之，这些数据定义了一种新的凝聚体，该课题组人员称之为协调体（C-body），并将C-body确立为白血病的治疗脆弱性。

据了解，在癌症发展过程中，突变促进基因表达的变化从而导致转化。与HOXA异常表达相关的白血病是由核孔蛋白基因或KMT2A易位以及NPM1突变驱动的。这些完全不同的突变的机制趋同仍然是未知的。

附：英文原文

Title: Disparate leukemia mutations converge on nuclear phase-separated condensates

Author: 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, Bjrn Tore Gjertsen, Brunangelo Falini, Rachel E. Rau, Lorenzo Brunetti, Nidhi Sahni, Margaret A. Goodell, Joshua A. Riback

Issue&Volume: 2025-11-04

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.

DOI: 10.1016/j.cell.2025.10.010

Source: https://www.cell.com/cell/abstract/S0092-8674(25)01149-3