作者
Bappaditya Chandra,Nicole L. Michmerhuizen,Hazheen K Shirnekhi,Swarnendu Tripathi,Brittany J Pioso,David W Baggett,Diana M Mitrea,Ilaria Iacobucci,Michael R White,Jingjing Chen,Cheon-Gil Park,Huiyun Wu,Stanley Pounds,Anna Medyukhina,Khaled Khairy,Qingsong Gao,Chunxu Qu,Sherif Abdelhamed,Scott D Gorman,Simranjot Bawa,Carolyn Maslanka,Swati Kinger,Priyanka Dogra,Mylene C Ferrolino,Danika Di Giacomo,Cristina Mecucci,Jeffery M. Klco,Charles G. Mullighan,Richard W. Kriwacki
摘要
NUP98 fusion oncoproteins (FOs) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid-liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98-HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form, and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98-PRRX1, NUP98-KDM5A, NUP98-LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs.