Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.
Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations.
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DOI：
10.1172/jci169993
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发表时间：
2023-07-03
影响因子：
15.9
通讯作者：
Shilatifard, Ali
中科院分区：
文献类型：
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作者：
Zhao, Zibo;Cao, Kaixiang;Watanabe, Jun;Philips, Cassandra N.;Zeidner, Jacob M.;Ishi, Yukitomo;Wang, Qixuan;Gold, Sarah R.;Junkins, Katherine;Bartom, Elizabeth T.;Yue, Feng;Chandel, Navdeep S.;Hashizume, Rintaro;Ben-Sahra, Issam;Shilatifard, Ali
染色质修饰酶的表观遗传状态改变突变是人类疾病的一个特征，包括许多癌症。然而，由这些突变引起的功能结果和细胞依赖性仍然没有得到解决。在这项研究中，我们研究了细胞的依赖性，或脆弱性，当增强子功能受到频繁突变的COMPASS家族成员MLL 3和MLL 4的损失的影响时。在MLL 3/4耗尽的小鼠胚胎干细胞（mESC）中的CRISPR缺失筛选揭示了在抑制嘌呤和嘧啶核苷酸合成途径后的合成致死性。因此，我们观察到MLL 3/4-KO mESC中代谢活性向嘌呤合成增加的转变。这些细胞还表现出对嘌呤合成抑制剂洛美沙星的敏感性增强，这诱导了独特的基因表达特征。RNA-Seq鉴定了与嘌呤代谢抑制一致的顶级MLL 3/4靶基因，并且串联质量标签蛋白质组分析进一步证实了MLL 3/4-KO细胞中嘌呤合成的上调。从机制上讲，我们证明了MLL 1/COMPASS的补偿是这些效应的基础。最后，我们证明了具有MLL 3和/或MLL 4突变的肿瘤在体外和体内对洛美沙星高度敏感，无论是在培养物中还是在癌症动物模型中。我们的研究结果描述了由表观遗传因子缺乏引起的靶向代谢依赖性，为MLL 3/4 COMPASS功能障碍继发表观遗传改变的癌症治疗提供了分子见解。
Epigenetic status–altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family members MLL3 and MLL4. CRISPR dropout screens in MLL3/4-depleted mouse embryonic stem cells (mESCs) revealed synthetic lethality upon suppression of purine and pyrimidine nucleotide synthesis pathways. Consistently, we observed a shift in metabolic activity toward increased purine synthesis in MLL3/4-KO mESCs. These cells also exhibited enhanced sensitivity to the purine synthesis inhibitor lometrexol, which induced a unique gene expression signature. RNA-Seq identified the top MLL3/4 target genes coinciding with suppression of purine metabolism, and tandem mass tag proteomic profiling further confirmed upregulation of purine synthesis in MLL3/4-KO cells. Mechanistically, we demonstrated that compensation by MLL1/COMPASS was underlying these effects. Finally, we demonstrated that tumors with MLL3 and/or MLL4 mutations were highly sensitive to lometrexol in vitro and in vivo, both in culture and in animal models of cancer. Our results depicted a targetable metabolic dependency arising from epigenetic factor deficiency, providing molecular insight to inform therapy for cancers with epigenetic alterations secondary to MLL3/4 COMPASS dysfunction.