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.

RNA 结合蛋白 (RBP) 在急性髓系白血病 (AML) 这种致命疾病中发挥着关键作用。尽管在 AML 中识别出具有特定相分离能力的 RBP，但其冷凝物形成对 AML 白血病发生的影响以及抑制相分离的治疗潜力尚未得到充分探索。在我们的体内 CRISPR RBP 筛选中，纤维蛋白 (FBL) 成为调节 AML 细胞存活的关键核仁蛋白，主要通过其相分离结构域而不是甲基转移酶或乙酰化结构域。这些具有特定功能的相分离结构域协调驱动核仁形成和前rRNA的早期加工（包括外排、裂解和甲基化），最终增强MYC等癌基因的翻译。使用 CGX-635 靶向 FBL 的相分离能力可消除 AML 细胞，这表明 CGX-635 的另一种作用机制可以补充其既定的治疗效果。我们强调关键蛋白的 PS 调节作为 AML 可能的治疗策略的潜力。