Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.

组蛋白赖氨酸 N-甲基转移酶 2A (KMT2Ar) 的重排与儿童、成人和治疗引起的急性白血病有关。患有 KMT2Ar 急性淋巴细胞白血病 (ALL) 的婴儿预后较差，无事件生存率为 38%。在此，我们评估了初级 KMT2Ar 婴儿 ALL 样本中的 1116 种 FDA 批准的化合物，并确定了对蛋白酶体抑制的敏感性。暴露于此类药物后，除了 KMT2A 基因表达特征下调外，细胞还表现出 KMT2A 靶基因处的组蛋白 H2B 单泛素化 (H2Bub1) 和组蛋白 H3 赖氨酸 79 二甲基化 (H3K79me2) 的消耗，这提供了证据表明它针对KMT2A 转录复合物并改变表观基因组。一组复发/难治性 KMT2Ar 患者在富有同情心的基础上接受这种方法治疗，总体缓解率为 90%。总之，我们报告了对原发性儿童白血病标本的高通量药物筛选，其结果转化为具有临床意义的反应。这种创新的治疗方法目前正在一项针对新诊断为 ALL 的婴儿的多机构前期试验中进行评估。