期刊
CANCER DISCOVERY
卷 12, 期 4, 页码 1152-1169出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0674
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资金
- NCI Cancer Center Support Grant [P30 CA021765]
- NCI Outstanding Investigator Award [R35 CA197695]
- NCI [T32 CA236748]
- National Institute of General Medical Sciences [F32 GM143847]
- Burroughs Wellcome Fund
- St. Jude Children's Research Hospital Chromatin Collaborative award
- Neoma Boadway Fellowship from St. Jude Children's Research Hospital
- St. Jude Summer Plus Fellowships from Rhodes College
- American Lebanese Syrian Associated Charities
- [NCI P30 CA021765]
NUP98 fusion oncoproteins (FO) 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, and NUP98-LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs. SIGNIFICANCE: We show that homotypic and heterotypic mechanisms of LLPS control NUP98-HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structure s. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis.
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