Phase separation-competent FBL promotes early pre-rRNA processing and translation in acute myeloid leukaemia.
Nat Cell Biol
; 26(6): 946-961, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38745030
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Precursores de RNA
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Proteínas Cromossômicas não Histona
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Leucemia Mieloide Aguda
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Processamento Pós-Transcricional do RNA
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article