Dotting out AML by targeting Fibrillarin

Abstract Dysregulated biomolecular condensates, formed through multivalent interactions among proteins and nucleic acids have been recently identified to drive tumorigenesis. In acute myeloid leukemia (AML), condensates driven by RNA-binding proteins (RBPs) alter transcriptional networks. Yang and colleagues performed a CRISPR screen and identified Fibrillarin (FBL) as a new driver in AML leukemogenesis. FBL depletion caused cell cycle arrest and death in AML cells, with minimal impact on normal cells. FBL's phase separation domains are essential for pre-rRNA processing, influencing AML cell survival by regulating ribosome biogenesis and the translation of oncogenic proteins like MYC. Therapeutically, the chemotherapeutic agent CGX-635 targets FBL, inducing its aggregation, impairing pre-rRNA processing, and reducing AML cell survival. This highlights FBL's phase separation as a therapeutic vulnerability in AML. These findings suggest that targeting the phase separation properties of RBPs could offer a novel and effective strategy for AML treatment. Further research into condensate dynamics in cancer and development of condensate-modulating drugs holds significant promise for future cancer therapies.