Gain-of-function mutations in the histone acetylation ‘reader’ ENL, found in AML and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis, and demonstrates the potential of targeting pathogenic condensates in cancer treatment.

中文翻译：

---

促凝 ENL 突变通过组蛋白修饰和基因表达的动态调节驱动体内肿瘤发生


在 AML 和肾母细胞瘤中发现的组蛋白乙酰化“读取器”ENL 中的功能获得性突变已知可驱动细胞系统中凝结物的形成和基因激活。然而，它们在肿瘤发生中的作用仍不清楚。使用条件敲入小鼠模型，我们发现突变的 ENL 扰乱正常造血，诱导骨髓祖细胞异常扩张，并引发侵袭性 AML 的快速发作。突变的 ENL 部分通过重塑组蛋白修饰来改变发育和炎症基因程序。突变的 ENL 在造血干/祖细胞的关键致白血病基因处形成凝聚物，通过诱变破坏凝聚物的形成会损害其染色质和致癌功能。此外，用突变型 ENL 的乙酰结合抑制剂进行治疗可以将这些缩合物从靶位点上取代，抑制突变型 ENL 诱导的染色质变化，并延迟体内 AML 的起始和进展。我们的研究阐明了 ENL 突变在染色质调节和肿瘤发生中的功能，并证明了在癌症治疗中靶向致病性浓缩物的潜力。