Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Microbiology and Immunology, Indiana University School of Medicine, 950 West Walnut Street, R2-302, Indianapolis, IN, 46202-5181, USA.
Leukemia. 2023 Jan;37(1):190-201. doi: 10.1038/s41375-022-01765-0. Epub 2022 Nov 26.
MLL (KMT2a) translocations are found in ~10% of acute leukemia patients, giving rise to oncogenic MLL-fusion proteins. A common MLL translocation partner is ENL and associated with a poor prognosis in t(11;19) patients. ENL contains a highly conserved N-terminal YEATS domain that binds acetylated histones and interacts with the PAF1c, an epigenetic regulator protein complex essential for MLL-fusion leukemogenesis. Recently, wild-type ENL, and specifically the YEATS domain, was shown to be essential for leukemic cell growth. However, the inclusion and importance of the YEATS domain in MLL-ENL-mediated leukemogenesis remains unexplored. We found the YEATS domain is retained in 84.1% of MLL-ENL patients and crucial for MLL-ENL-mediated leukemogenesis in mouse models. Mechanistically, deletion of the YEATS domain impaired MLL-ENL fusion protein binding and decreased expression of pro-leukemic genes like Eya1 and Meis1. Point mutations that disrupt YEATS domain binding to acetylated histones decreased stem cell frequency and increased MLL-ENL-mediated leukemia latency. Therapeutically, YEATS containing MLL-ENL leukemic cells display increased sensitivity to the YEATS inhibitor SGC-iMLLT compared to control AML cells. Our results demonstrate that the YEATS domain is important for MLL-ENL fusion protein-mediated leukemogenesis and exposes an "Achilles heel" that may be therapeutically targeted for treating t(11;19) patients.
MLL（KMT2a）易位发生在约 10%的急性白血病患者中，导致致癌性的 MLL 融合蛋白的产生。一个常见的 MLL 易位伙伴是 ENL，与 t(11;19)患者的不良预后相关。ENL 含有一个高度保守的 N 端 YEATS 结构域，该结构域与乙酰化组蛋白结合，并与 PAF1c 相互作用，PAF1c 是一种表观遗传调节蛋白复合物，对于 MLL 融合白血病的发生是必不可少的。最近，野生型 ENL，特别是 YEATS 结构域，被证明对白血病细胞的生长是必不可少的。然而，YEATS 结构域在 MLL-ENL 介导的白血病发生中的包含和重要性仍未被探索。我们发现 YEATS 结构域在 84.1%的 MLL-ENL 患者中被保留，并且对小鼠模型中的 MLL-ENL 介导的白血病发生至关重要。从机制上讲，删除 YEATS 结构域会损害 MLL-ENL 融合蛋白的结合，并降低 Eya1 和 Meis1 等促白血病基因的表达。破坏 YEATS 结构域与乙酰化组蛋白结合的点突变会降低干细胞频率并增加 MLL-ENL 介导的白血病潜伏期。在治疗方面，与对照 AML 细胞相比，含有 YEATS 结构域的 MLL-ENL 白血病细胞对 YEATS 抑制剂 SGC-iMLLT 的敏感性增加。我们的研究结果表明，YEATS 结构域对于 MLL-ENL 融合蛋白介导的白血病发生很重要，并揭示了一个可能成为治疗 t(11;19)患者的治疗靶点的“阿喀琉斯之踵”。
