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.

中文翻译：

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通过靶向纤维蛋白来消除 AML


最近发现，通过蛋白质和核酸之间的多价相互作用形成的失调的生物分子凝聚物可驱动肿瘤发生。在急性髓系白血病 (AML) 中，RNA 结合蛋白 (RBP) 驱动的冷凝物会改变转录网络。 Yang 及其同事进行了 CRISPR 筛选，并确定 Fibrillarin (FBL) 是 AML 白血病发生的新驱动因素。 FBL 耗尽导致 AML 细胞的细胞周期停滞和死亡，对正常细胞的影响最小。 FBL 的相分离结构域对于 rRNA 前体加工至关重要，通过调节核糖体生物合成和 MYC 等致癌蛋白的翻译来影响 AML 细胞的存活。在治疗上，化疗药物 CGX-635 以 FBL 为靶点，诱导其聚集，损害 pre-rRNA 加工，并降低 AML 细胞的存活率。这凸显了 FBL 的相分离作为 AML 的治疗弱点。这些发现表明，针对 RBP 的相分离特性可以为 AML 治疗提供一种新颖且有效的策略。对癌症中凝聚态动力学的进一步研究和凝聚态调节药物的开发为未来的癌症治疗带来了巨大的希望。