合并遗传筛选是识别癌症易感性的强大方法。我们在这里使用了合并CRISPR/Cas9为基础的方法来识别与超过80%的胶质母细胞瘤中发现的端粒酶逆转录酶(TERT)启动子突变(TPM)相关的易感性。我们首先开发了一个平台，用于检测导致TPM突变胶质母细胞瘤细胞系长期生长缺陷的混乱。然而，我们无法检测到对TERT本身或已知激活TPM的E-26转录因子的依赖性。为了探索这一发现，我们对441个细胞系的TPM状态进行了目录化，并将其与全基因组筛选数据进行了相关性分析。我们发现，TPM状态与TERT的差异依赖性无关，但E-26转录因子在TPM阳性和TPM阴性细胞系中都是关键的依赖性。此外，我们发现TPM与细胞系和原发性胶质母细胞瘤组织中由广泛的ETS因子调控的基因程序的表达相关。这项工作提供了一种独特的TPM细胞系试剂，为许多深入分析的细胞系建立了TPM状态，并对与TPM相关的易感性进行了目录化。结果突显了执行遗传筛选以检测特定TPM易感性的挑战，并暗示了调节TPM功能的遗传网络中的冗余，具有治疗意义。 © 2023. 作者授予Springer Nature Limited独家许可权。

Pooled genetic screens represent a powerful approach to identify vulnerabilities in cancer. Here we used pooled CRISPR/Cas9-based approaches to identify vulnerabilities associated with telomerase reverse transcriptase (TERT) promoter mutations (TPMs) found in >80% of glioblastomas. We first developed a platform to detect perturbations that cause long-term growth defects in a TPM-mutated glioblastoma cell line. However, we could not detect dependencies on either TERT itself or on an E-twenty six transcription (ETS) factor known to activate TPMs. To explore this finding, we cataloged TPM status for 441 cell lines and correlated this with genome-wide screening data. We found that TPM status was not associated with differential dependency on TERT, but that E-twenty six (ETS) transcription factors represent key dependencies in both TPM+ and TPM- lines. Further, we found that TPMs are associated with expression of gene programs regulated by a wide array of ETS-factors in both cell lines and primary glioblastoma tissues. This work contributes a unique TPM cell line reagent, establishes TPM status for many deeply-profiled cell lines, and catalogs TPM-associated vulnerabilities. The results highlight challenges in executing genetic screens to detect TPM-specific vulnerabilities, and suggest redundancy in the genetic network that regulates TPM function with therapeutic implications.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.