T细胞急性淋巴细胞白血病（T-ALL）的一个显著特征是癌基因转录因子（TFs）的异常表达，包括TAL1、NOTCH1和MYC。转录程序的重塑破坏了下游靶基因的严格控制的时空表达，从而有助于白血病发生。在本研究中，我们首次发现一个被称为enhMYCN的在T-ALL细胞中被TAL1复合物异常激活的具有进化保守性的增强子元件来控制MYCN癌基因的表达。TAL1阳性的T-ALL细胞对MYCN表达在体外和异种移植模型中的维持高度依赖。有趣的是，MYCN促进甲萘醇代谢途径中多个基因的表达，而T-ALL细胞对HMG-CoA还原酶（HMGCR）的抑制则敏感，HMGCR是此途径的速限酶。重要的是，MYC和MYCN调控相同的靶基因并相互补偿。因此，MYCN阳性的T-ALL细胞在TAL1-MYCN和NOTCH1-MYC通路上表现出双重依赖。综上，我们的结果表明，通过enhMYCN介导的MYCN表达对人类T-ALL细胞是必需的，并将TAL1-MYCN-HMGCR轴作为T-ALL的潜在治疗靶点。© 2023。作者（们）在Springer Nature有限公司独家许可下发表。

A hallmark of T-cell acute lymphoblastic leukemia (T-ALL) is the dysregulated expression of oncogenic transcription factors (TFs), including TAL1, NOTCH1 and MYC. Rewiring of the transcriptional program disrupts the tightly controlled spatiotemporal expression of downstream target genes, thereby contributing to leukemogenesis. In this study, we first identify an evolutionarily conserved enhancer element controlling the MYCN oncogene (named enhMYCN) that is aberrantly activated by the TAL1 complex in T-ALL cells. TAL1-positive T-ALL cells are highly dependent on MYCN expression for their maintenance in vitro and in xenograft models. Interestingly, MYCN drives the expression of multiple genes involved in the mevalonate pathway, and T-ALL cells are sensitive to inhibition of HMG-CoA reductase (HMGCR), a rate-limiting enzyme of this pathway. Importantly, MYC and MYCN regulate the same targets and compensate for each other. Thus, MYCN-positive T-ALL cells display a dual dependence on the TAL1-MYCN and NOTCH1-MYC pathways. Together, our results demonstrate that enhMYCN-mediated MYCN expression is required for human T-ALL cells and implicate the TAL1-MYCN-HMGCR axis as a potential therapeutic target in T-ALL.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.