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.
- Nature Cell Biology, 26(6), 946-961, 2024. .
Artículo
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.
CRISPR ASSOCIATED PROTEIN
FIBRILLARIN
FLUOROURACIL
HOMOHARRINGTONINE
METHYLTRANSFERASE
MYC PROTEIN
RIBOSOME RNA
RNA BINDING PROTEIN
FIBRILLARIN
NONHISTONE PROTEIN
RNA BINDING PROTEIN
Artículo
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.
CRISPR ASSOCIATED PROTEIN
FIBRILLARIN
FLUOROURACIL
HOMOHARRINGTONINE
METHYLTRANSFERASE
MYC PROTEIN
RIBOSOME RNA
RNA BINDING PROTEIN
FIBRILLARIN
NONHISTONE PROTEIN
RNA BINDING PROTEIN