Gambi Giovanni, Boccalatte Francesco, Rodriguez Hernaez Javier, Lin Ziyan, Nadorp Bettina, Polyzos Alexander, Tan Jimin, Avrampou Kleopatra, Inghirami Giorgio, Kentsis Alex, Apostolou Effie, Aifantis Iannis, Tsirigos Aristotelis
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA; Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA.
Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA; Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY, USA; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy.
Mol Cell. 2025 Jan 2;85(1):42-60.e7. doi: 10.1016/j.molcel.2024.11.040. Epub 2024 Dec 23.
Cancer progression involves genetic and epigenetic changes that disrupt chromatin 3D organization, affecting enhancer-promoter interactions and promoting growth. Here, we provide an integrative approach, combining chromatin conformation, accessibility, and transcription analysis, validated by in silico and CRISPR-interference screens, to identify relevant 3D topologies in pediatric T cell leukemia (T-ALL and ETP-ALL). We characterize 3D hubs as regulatory centers for oncogenes and disease markers, linking them to biological processes like cell division, inflammation, and stress response. Single-cell mapping reveals heterogeneous gene activation in discrete epigenetic clones, aiding in patient stratification for relapse risk after chemotherapy. Finally, we identify MYB as a 3D hub regulator in leukemia cells and show that the targeting of key regulators leads to hub dissolution, thereby providing a novel and effective anti-leukemic strategy. Overall, our work demonstrates the relevance of studying oncogenic 3D hubs to better understand cancer biology and tumor heterogeneity and to propose novel therapeutic strategies.
癌症进展涉及破坏染色质三维组织的遗传和表观遗传变化，影响增强子-启动子相互作用并促进生长。在此，我们提供了一种综合方法，结合染色质构象、可及性和转录分析，并通过计算机模拟和CRISPR干扰筛选进行验证，以识别小儿T细胞白血病（T-ALL和ETP-ALL）中相关的三维拓扑结构。我们将三维枢纽表征为癌基因和疾病标志物的调控中心，将它们与细胞分裂、炎症和应激反应等生物学过程联系起来。单细胞图谱揭示了离散表观遗传克隆中的异质基因激活，有助于对化疗后复发风险的患者进行分层。最后，我们确定MYB为白血病细胞中的三维枢纽调节因子，并表明靶向关键调节因子会导致枢纽解体，从而提供一种新颖有效的抗白血病策略。总体而言，我们的工作证明了研究致癌三维枢纽对于更好地理解癌症生物学和肿瘤异质性以及提出新颖治疗策略的相关性。
