1. Academic Validation
  2. Phase separation-competent FBL promotes early pre-rRNA processing and translation in acute myeloid leukaemia

Phase separation-competent FBL promotes early pre-rRNA processing and translation in acute myeloid leukaemia

  • Nat Cell Biol. 2024 May 14. doi: 10.1038/s41556-024-01420-z.
Lin Yang # 1 2 3 Zhaoru Zhang # 1 2 4 Penglei Jiang 1 2 4 Delin Kong 1 2 4 Zebin Yu 1 Danrong Shi 5 Yingli Han 1 2 4 Ertuo Chen 1 Weiyan Zheng 4 6 Jie Sun 4 6 Yanmin Zhao 2 4 6 Yi Luo 2 4 6 Jimin Shi 2 4 6 Hangping Yao 5 He Huang 7 8 9 Pengxu Qian 10 11 12
Affiliations

Affiliations

  • 1 Bone Marrow Transplantation Center of the First Affiliated Hospital, and Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
  • 3 State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University & Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China.
  • 4 Institute of Hematology, Zhejiang University & Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China.
  • 5 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 6 Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Liangzhu Laboratory, Zhejiang University, Hangzhou, China. [email protected].
  • 8 Institute of Hematology, Zhejiang University & Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China. [email protected].
  • 9 Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 10 Bone Marrow Transplantation Center of the First Affiliated Hospital, and Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 11 Liangzhu Laboratory, Zhejiang University, Hangzhou, China. [email protected].
  • 12 State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University & Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China. [email protected].
  • # Contributed equally.
Abstract

RNA-binding proteins (RBPs) are pivotal in acute myeloid leukaemia (AML), a lethal disease. Although specific phase separation-competent RBPs are recognized in AML, the effect of their condensate formation on AML leukaemogenesis, and the therapeutic potential of inhibition of phase separation are underexplored. In our in vivo CRISPR RBP screen, fibrillarin (FBL) emerges as a crucial nucleolar protein that regulates AML cell survival, primarily through its phase separation domains rather than methyltransferase or acetylation domains. These phase separation domains, with specific features, coordinately drive nucleoli formation and early processing of pre-rRNA (including efflux, cleavage and methylation), eventually enhancing the translation of oncogenes such as MYC. Targeting the phase separation capability of FBL with CGX-635 leads to elimination of AML cells, suggesting an additional mechanism of action for CGX-635 that complements its established therapeutic effects. We highlight the potential of PS modulation of critical proteins as a possible therapeutic strategy for AML.

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