Acute myeloid leukemia (AML) remains challenging to treat, which in part relates to genetic heterogeneity of the disease, to the protective tumor microenvironment driving resistance to therapy, and also to immune evasion characteristics of leukemic cells. Targeting epigenetic programs in AML provides an attractive opportunity to impair long-term proliferation and induce differentiation. The novel inhibitor JNJ- 75276617 (bleximenib) targets the menin-KMT2A interaction and provides preclinical efficacy in AML (Kwon et al1). Here, we provide mechanistic insight in how JNJ- 75276617 impairs proliferation and drives differentiation of primary AML patient cells. A large-scale drug screen was set up in which genetic alterations and quantitative proteomics were compared with drug sensitivity in a preclinical setting, which revealed that granulocyte macrophage progenitor (GMP)-like AMLs display the greatest sensitivity. Furthermore, we identified that NPM1c/DNMT3Amut AMLs are sensitive, and some NPM1wt AML subtypes without KMT2A-MLLT3 rearrangements benefit from menin-KMT2A inhibition. Genome-wide ChIP-seq studies revealed patient-specific epigenetic alterations upon JNJ-75276617 treatment, uncovering a striking upregulation of MHC class I and class II expression as a consequence of epigenetic changes upon menin-KMT2A inhibition, independent of MEIS1 loss but involving CIITA activation. Functionally, this results in enhanced sensitivity of leukemic blasts to T cell-mediated cytotoxicity in allogeneic and autologous settings. Our data indicate that JNJ-75276617 provides a potential therapeutic approach whereby not only proliferation is impaired and differentiation is induced, but whereby therapeutic benefit might also be achieved by reactivating the antigen presentation machinery.

中文翻译：

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Bleximenib 是一种新型 menin-KMT2A 抑制剂 JNJ-75276617，可损害急性髓性白血病的长期增殖和免疫逃逸。


急性髓系白血病 （AML） 仍然难以治疗，这部分与疾病的遗传异质性、导致治疗耐药性的保护性肿瘤微环境以及白血病细胞的免疫逃避特性有关。在 AML 中靶向表观遗传程序为损害长期增殖和诱导分化提供了一个有吸引力的机会。新型抑制剂 JNJ-75276617 （bleximenib） 靶向 menin-KMT2A 相互作用，并在 AML 中提供临床前疗效 （Kwon et al1）。在这里，我们提供了关于 JNJ- 75276617 如何损害增殖并驱动原发性 AML 患者细胞分化的机制见解。建立了一项大规模药物筛选，其中遗传改变和定量蛋白质组学与临床前环境中的药物敏感性进行了比较，结果显示粒细胞巨噬细胞祖细胞 （GMP） 样 AML 表现出最大的敏感性。此外，我们发现 NPM1c/DNMT3Amut AMLs 是敏感的，一些没有 KMT2A-MLLT3 重排的 NPM1wt AML 亚型受益于 menin-KMT2A 抑制。全基因组 ChIP-seq 研究揭示了 JNJ-75276617 治疗后患者特异性的表观遗传改变，揭示了 MHC I 类和 II 类表达的显着上调，这是 menin-KMT2A 抑制后表观遗传变化的结果，独立于 MEIS1 丢失，但涉及 CIITA 激活。在功能上，这导致白血病原始细胞在同种异体和自体环境中对 T 细胞介导的细胞毒性的敏感性增强。 我们的数据表明，JNJ-75276617 提供了一种潜在的治疗方法，不仅可以损害增殖并诱导分化，而且还可以通过重新激活抗原呈递机制来实现治疗益处。