Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
Department of Pathology, University of Illinois Chicago, Chicago, Illinois.
Cancer Res. 2022 Oct 17;82(20):3763-3773. doi: 10.1158/0008-5472.CAN-22-1215.
Peripheral T-cell lymphomas (PTCL) are agressive lymphomas that develop from mature T cells. The most common PTCLs are genetically, molecularly, and clinically diverse and are generally associated with dismal outcomes. While Notch signaling plays a critically important role in both the development of immature T cells and their malignant transformation, its role in PTCL is poorly understood, despite the increasingly appreciated function of Notch in regulating the proliferation and differentiation of mature T cells. Here, we demonstrate that Notch receptors and their Delta-like family ligands (DLL1/DLL4) play a pathogenic role in PTCL. Notch1 activation was observed in common PTCL subtypes, including PTCL-not otherwise specified (NOS). In a large cohort of PTCL-NOS biopsies, Notch1 activation was significantly associated with surrogate markers of proliferation. Complementary genetically engineered mouse models and spontaneous PTCL models were used to functionally examine the role of Notch signaling, and Notch1/Notch2 blockade and pan-Notch blockade using dominant-negative MAML significantly impaired the proliferation of malignant T cells and PTCL progression in these models. Treatment with DLL1/DLL4 blocking antibodies established that Notch signaling is ligand-dependent. Together, these findings reveal a role for ligand-dependent Notch signaling in driving peripheral T-cell lymphomagenesis.
This work demonstrates that ligand-dependent Notch activation promotes the growth and proliferation of mature T-cell lymphomas, providing new therapeutic strategies for this group of aggressive lymphomas.
外周 T 细胞淋巴瘤（PTCL）是一种来源于成熟 T 细胞的侵袭性淋巴瘤。最常见的 PTCL 在遗传、分子和临床方面具有多样性，通常与预后不良相关。尽管 Notch 信号在不成熟 T 细胞的发育及其恶性转化中起着至关重要的作用，但 Notch 在 PTCL 中的作用仍知之甚少，尽管 Notch 在调节成熟 T 细胞的增殖和分化方面的功能日益受到重视。在这里，我们证明 Notch 受体及其 Delta 样家族配体（DLL1/DLL4）在外周 T 细胞淋巴瘤中发挥致病作用。常见的 PTCL 亚型包括未特指的 PTCL（NOS）中观察到 Notch1 激活。在 PTCL-NOS 活检的大队列中，Notch1 激活与增殖的替代标志物显著相关。互补的基因工程小鼠模型和自发性 PTCL 模型用于功能检查 Notch 信号的作用，Notch1/Notch2 阻断和泛 Notch 阻断使用显性负性 MAML 显著损害这些模型中恶性 T 细胞的增殖和 PTCL 进展。DLL1/DLL4 阻断抗体的治疗表明 Notch 信号是配体依赖性的。总之，这些发现揭示了配体依赖性 Notch 信号在外周 T 细胞淋巴瘤发生中的作用。
这项工作表明，配体依赖性 Notch 激活促进了成熟 T 细胞淋巴瘤的生长和增殖，为这组侵袭性淋巴瘤提供了新的治疗策略。
