Egan Grace, Tasian Sarah K
Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
Blood. 2025 May 29;145(22):2574-2586. doi: 10.1182/blood.2024026598.
Robust genetic characterization of pediatric acute myeloid leukemia (AML) has demonstrated that fusion oncogenes are highly prevalent drivers of AML leukemogenesis in young children. Identification of fusion oncogenes associated with adverse outcomes has facilitated risk stratification of patients, although successful development of precision medicine approaches for most fusion-driven AML subtypes have been historically challenging. This knowledge gap has been in part due to difficulties in targeting structural alterations involving transcription factors and in identification of a therapeutic window for selective inhibition of the oncofusion without deleterious effects upon essential wild-type proteins. Herein, we discuss the current molecular landscape and functional characterization of 3 of the most lethal childhood AML fusion-oncogene driven subtypes harboring KMT2A, NUP98, or CBFA2T3::GLIS2 rearrangements. We further review early-phase clinical trial data of novel targeted inhibitors and immunotherapies that have demonstrated initial success specifically for children with these poor-prognosis genetic subtypes of AML and provide appreciable optimism to improve clinical outcomes in the future.
对小儿急性髓系白血病（AML）进行的强有力的基因特征分析表明，融合致癌基因是幼儿AML白血病发生的高度普遍驱动因素。与不良预后相关的融合致癌基因的鉴定有助于对患者进行风险分层，尽管从历史上看，针对大多数融合驱动的AML亚型成功开发精准医学方法一直具有挑战性。这一知识空白部分是由于难以靶向涉及转录因子的结构改变，以及难以确定在不对必需的野生型蛋白产生有害影响的情况下选择性抑制致癌融合的治疗窗口。在此，我们讨论了3种最致命的儿童AML融合致癌基因驱动亚型（携带KMT2A、NUP98或CBFA2T3::GLIS2重排）的当前分子格局和功能特征。我们进一步回顾了新型靶向抑制剂和免疫疗法的早期临床试验数据，这些数据已证明对患有这些预后不良的AML基因亚型的儿童具有初步成功，并为未来改善临床结果提供了可观的乐观前景。
