组蛋白 H3 赖氨酸 4 (H3K4) 甲基转移酶 KMT2D（也称为 MLL4）是髓母细胞瘤 (MB) 和其他类型癌症中最常见突变的表观遗传修饰因子之一。值得注意的是，KMT2D 杂合缺失在 MB 和其他癌症类型中普遍存在。然而，杂合性 KMT2D 缺失在肿瘤发生中所起的作用尚未得到很好的表征。在这里，我们发现，小鼠中 MB 抑制基因 Ptch 的杂合性缺失导致 Kmt2d 杂合缺失高度促进 MB。在 Ptch 突变驱动的 MB 发生中，杂合 Kmt2d 缺失上调了促肿瘤程序，包括氧化磷酸化和 G 蛋白偶联受体信号传导。从机制上讲，杂合子 Kmt2d 缺失导致转录抑制性肿瘤抑制基因 NCOR2 下调，杂合子 Ptch 缺失导致癌基因 MycN 上调，均增加了促癌基因的表达。此外，杂合的 Kmt2d 缺失大大削弱了增强子信号（例如 H3K27ac）和 H3K4me3 信号，包括肿瘤抑制基因的信号（例如 Ncor2）。氧化磷酸化和 H3K4 去甲基酶 LSD1 的联合药理抑制可显着降低具有杂合 Kmt2d 缺失的 MB 细胞的致瘤性。这些发现揭示了杂合子 KMT2D 缺失的 MB 促进作用的机制基础，为治疗 KMT2D 缺陷型 MB 的治疗策略提供了理论基础，并对具有杂合子 KMT2D 缺失的其他类型癌症的分子发病机制具有机制意义。

The histone H3 lysine 4 (H3K4) methyltransferase KMT2D (also called MLL4) is one of the most frequently mutated epigenetic modifiers in medulloblastoma (MB) and other types of cancer. Notably, heterozygous loss of KMT2D is prevalent in MB and other cancer types. However, what role heterozygous KMT2D loss plays in tumorigenesis has not been well characterized. Here, we show that heterozygous Kmt2d loss highly promotes MB driven by heterozygous loss of the MB suppressor gene Ptch in mice. Heterozygous Kmt2d loss upregulated tumor-promoting programs, including oxidative phosphorylation and G-protein-coupled receptor signaling, in Ptch-mutant-driven MB genesis. Mechanistically, both downregulation of the transcription-repressive tumor suppressor gene NCOR2 by heterozygous Kmt2d loss and upregulation of the oncogene MycN by heterozygous Ptch loss increased the expression of tumor-promoting genes. Moreover, heterozygous Kmt2d loss extensively diminished enhancer signals (e.g., H3K27ac) and H3K4me3 signature, including those for tumor suppressor genes (e.g., Ncor2). Combinatory pharmacological inhibition of oxidative phosphorylation and the H3K4 demethylase LSD1 drastically reduced tumorigenicity of MB cells bearing heterozygous Kmt2d loss. These findings reveal the mechanistic basis underlying the MB-promoting effect of heterozygous KMT2D loss, provide a rationale for a therapeutic strategy for treatment of KMT2D-deficient MB, and have mechanistic implications for the molecular pathogenesis of other types of cancer bearing heterozygous KMT2D loss.