Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
Oncogene. 2014 Dec 11;33(50):5655-65. doi: 10.1038/onc.2013.565. Epub 2014 Jan 27.
The discovery of constitutive nuclear factor-κB (NF-κB) activation in Hodgkin's lymphoma tumor cells almost two decades ago was one of the first reports that directly connected deregulated NF-κB signaling to human cancer. Subsequent studies demonstrated that enhanced NF-κB signaling is a common hallmark of many lymphoid malignancies, including Hodgkin lymphoma, mucosa-associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and multiple myeloma. By inducing an anti-apoptotic and pro-proliferative gene program, NF-κB is involved in lymphoma survival and growth. Identification of somatic mutations that led to activation of oncogenes and inactivation of tumor suppressor genes in the pathway revealed that specific pathogenic mechanisms are responsible for constitutive NF-κB activation in different lymphoma entities. Thus, the identification of distinct oncogenic events is reflecting the diverse cellular origins of the different lymphomas. Further, elucidation of the mechanisms that drive NF-κB in lymphoma is of high clinical relevance as it will allow the design of target-directed precision therapy. Indeed, a number of drugs that impair constitutive NF-κB activation in lymphoid malignancies are currently in preclinical or clinical development.
近二十年前，人们首次发现霍奇金淋巴瘤肿瘤细胞中组成性核因子-κB（NF-κB）的激活，这一发现直接将 NF-κB 信号的失调与人类癌症联系起来。随后的研究表明，增强的 NF-κB 信号是许多淋巴恶性肿瘤的共同特征，包括霍奇金淋巴瘤、黏膜相关淋巴组织淋巴瘤、弥漫性大 B 细胞淋巴瘤和多发性骨髓瘤。NF-κB 通过诱导抗凋亡和促增殖基因程序，参与淋巴瘤的存活和生长。该通路中导致致癌基因激活和肿瘤抑制基因失活的体细胞突变的鉴定表明，特定的发病机制负责不同淋巴瘤实体中组成性 NF-κB 的激活。因此，不同致癌事件的鉴定反映了不同淋巴瘤的不同细胞起源。此外，阐明驱动淋巴瘤中 NF-κB 的机制具有重要的临床意义，因为它将允许设计针对特定靶点的精准治疗。事实上，目前有许多药物正在临床前或临床开发中，旨在抑制淋巴恶性肿瘤中组成性 NF-κB 的激活。
