In an era of precision medicine, oncogenic transcription factors remain notoriously difficult to target. With the notable exception of PML-RARA, expressed in many promyelocytic leukemias, which can be inactivated by retinoic acid, there exist few targeted therapies for tumors expressing an activated, oncogenic transcription factor. An example is adenoid cystic carcinoma (ACC) bearing the recurrent t(6;9) translocation, in which the MYB oncogene on chromosome 6 becomes fused to the NFIB gene on chromosome 9 (1,2). The result is a highly expressed MYB gene, driven by enhancers from the NFIB fusion partner (3). The broken fusion gene also expresses truncated variants of the Myb protein lacking the C-terminal-negative regulatory domains that are likely activated and oncogenic (4–6). The t(6;9) MYB-NFIB fusion occurs in about half of salivary gland ACC. A smaller fraction contains fusions of the related MYBL1 gene instead (6,7), suggesting that the activated Myb transcription factors encoded by MYB or MYBL1 are the driver oncogenes for these tumors. Indeed, the tumors that overexpress MYB but lack a frank translocation may utilize other mechanisms, such as alternative RNA splicing, to express truncated Myb proteins (6,8,9). Unfortunately, despite detailed whole-exome and whole-genome sequencing, no other recurrent mutations, and no readily targeted lesions such as activated tyrosine kinases, have been reproducibly detected in ACC (10–13). The combined evidence suggests that the chromosomal translocations in ACC play the dual role of truncating and activating the MYB or MYBL1 genes, and also fusing the oncogenes to strong tissue-specific enhancers from the NFIB gene or other less frequent fusion partners (3,6,7,14). A similar mechanism appears to lead to the overexpression of truncated MYB genes in gliomas (15,16). Thus, determining how the donated enhancers activate the promoters of the MYB or MYBL1 genes could lead to novel strategies for treating ACC tumors, the second most common type of salivary gland tumor, which has a dismal prognosis once it progresses to metastases (2,17).

中文翻译：

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社论：针对腺样囊性癌的MYB癌基因表达。

在精密医学时代，致癌转录因子仍然很难靶向。除了在许多早幼粒细胞白血病中表达的PML-RARA（可以被视黄酸灭活）外，针对表达活化的致癌转录因子的肿瘤的靶向治疗很少。一个例子是带有复发性t（6; 9）易位的腺样囊性癌（ACC），其中6号染色体上的MYB癌基因与9号染色体上的NFIB基因融合（1,2）。结果是由NFIB增强子驱动的高表达MYB基因融合伙伴（3）。断裂的融合基因还表达了Myb蛋白的截短变异体，该变异体缺少可能被激活和致癌的C端负调控域（4–6）。t（6; 9）MYB-NFIB融合发生在唾液腺ACC的大约一半中。较小部分包含相关MYBL1基因的融合体（6,7），表明MYB或MYBL1编码的激活的Myb转录因子是这些肿瘤的驱动癌基因。确实，过表达MYB的肿瘤但缺乏坦率的易位可能会利用其他机制（例如替代RNA剪接）来表达截短的Myb蛋白（6、8、9）。不幸的是，尽管进行了详细的全外显子组和全基因组测序，但在ACC中未可重现检测到其他复发突变，也未发现可靶向的病灶，例如活化的酪氨酸激酶（10-13）。综合证据表明，ACC中的染色体易位起着截断和激活MYB或MYBL1基因的双重作用，并且还将癌基因融合到了来自NFIB基因或其他不常见融合伴侣的强大的组织特异性增强子上（3,6， 7,14）。类似的机制似乎导致截短的MYB过表达胶质瘤中的基因（15,16）。因此，确定捐赠的增强子如何激活MYB或MYBL1基因的启动子可能会导致治疗ACC肿瘤的新策略，ACC肿瘤是唾液腺肿瘤的第二大类型，一旦进展为转移，预后就很差（2,17 ）。