基因表达的精确调控对于生物体的正常发育和维持体内平衡至关重要。研究表明，一些转录调节蛋白通过形成动态的、局部集中的组装体（称为冷凝物）来影响基因表达，而转录冷凝物的失调与多种癌症有关，例如尤文肉瘤和 AML [Wang Y et al. 2017]。 (2023) 自然化学生物学 19, 1223-1234;钱德拉 B 等人。 (2022) 癌症发现 12, 1152-1169]。组蛋白乙酰化“阅读器”11-19-白血病 (ENL) 中的突变已被证明在内源基因组靶标处形成离散的凝聚体，但目前尚不清楚 ENL 突变如何驱动肿瘤发生以及它是否与其凝聚体形成特性相关。刘等人。现在，使用条件敲入小鼠模型表明，ENL YEATS 结构域突变是 AML 真正的致癌驱动因素。这种突变的 ENL 在造血干/祖细胞中关键致白血病基因（包括 Meis1 和 Hoxa 簇基因）的基因组位点处形成凝聚物，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，他们还表明，乙酰结合活性的小分子抑制可以取代致癌靶位点的 ENL 突变体凝聚物，并且这种抑制剂可显着损害体内突变 ENL 驱动的 AML 的发生和进展。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Precise regulation of gene expression is essential for proper development and the maintenance of homeostasis in organisms. Studies have shown that some transcriptional regulatory proteins influence gene expression through the formation of dynamic, locally concentrated assemblies known as condensates, while dysregulation of transcriptional condensates was associated with several cancers, such as Ewing sarcoma and AML [Wang Y et al. (2023) Nat Chem Biol 19, 1223-1234; Chandra B et al. (2022) Cancer Discov 12, 1152-1169]. Mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL) have been shown to form discrete condensates at endogenous genomic targets, but it remains unclear how ENL mutations drive tumorigenesis and whether it is correlated with their condensate formation property. Liu et al. now show, using a conditional knock-in mouse model, that ENL YEATS domain mutation is a bona fide oncogenic driver for AML. This mutant ENL forms condensates in hematopoietic stem/progenitor cells at the genomic loci of key leukemogenic genes, including Meis1 and Hoxa cluster genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Furthermore, they show that small-molecule inhibition of the acetyl-binding activity displaces ENL mutant condensates from oncogenic target loci, and this inhibitor significantly impairs the onset and progression of AML driven by mutant ENL in vivo.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.