Targeting processive transcription for Myc-driven circuitry in medulloblastoma.

IF 16.4 1区医学 Q1 CLINICAL NEUROLOGY

Neuro-oncology Pub Date : 2025-05-15 DOI:10.1093/neuonc/noaf121

Lays Martin Sobral, Faye M Walker, Krishna Madhavan, Elizabeth Janko, Sahiti Donthula, Etienne Danis, Pradeep Bompada, Ilango Balakrishnan, Dong Wang, Angela Pierce, Mary M Haag, Billie J Carstens, Natalie J Serkova, Nicholas K Foreman, Sujatha Venkataraman, Bethany Veo, Rajeev Vibhakar, Nathan A Dahl

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引用次数: 0

Abstract

Background: Medulloblastoma is the most common malignant brain tumor of childhood. The highest-risk tumors are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB.

Methods: Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with CDK9/7 inhibitors to evaluate effect on Myc-driven programs and tumor growth.

Results: Eight CRISPR-Cas9 screens performed across three independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cells are susceptible to CDK9 inhibition, which is synergistic with concurrent inhibition of CDK7. Inhibition of transcriptional CDKs disrupts enhancer-promoter activity in Myc-MB and downregulates Myc-driven transcriptional programs, exerting potent anti-tumor effect.

Conclusions: Our findings identify CDK9 inhibition as a translationally promising strategy for the treatment of Myc-MB.

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髓母细胞瘤中myc驱动电路的靶向过程转录。

背景：髓母细胞瘤是儿童最常见的恶性脑肿瘤。风险最高的肿瘤是由复发性Myc扩增（Myc- mb）驱动的，尽管进行了强化的多模式治疗，但预后较差。Myc转录因子定义了这些肿瘤的核心调控回路，并广泛地放大下游促生存转录程序。直接靶向治疗Myc已被证明是难以捉摸的，但抑制转录辅助因子可能是一种间接的药物治疗维持Myc- mb的致癌转录通路的方法。方法：对独立的CRISPR-Cas9筛选进行汇总，以鉴定Myc-MB中的保守依赖性。我们对原发患者Myc-MB样本进行了染色质构象捕获（Hi-C），以绘制增强子-启动子相互作用图谱。然后，我们用CDK9/7抑制剂处理体外和异种移植模型，以评估对myc驱动程序和肿瘤生长的影响。结果：在三个独立的实验室进行的8次CRISPR-Cas9筛选确定CDK9在Myc-MB中是保守依赖性的。Myc-MB细胞易受CDK9抑制，这与CDK7的并发抑制是协同的。抑制转录CDKs破坏Myc-MB的增强子-启动子活性，下调myc驱动的转录程序，发挥有效的抗肿瘤作用。结论：我们的研究结果确定CDK9抑制是治疗Myc-MB的一种有翻译前景的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.