Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Nat Med. 2012 Nov;18(11):1699-704. doi: 10.1038/nm.2966. Epub 2012 Oct 14.
Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.
间变大细胞淋巴瘤（ALCL）是一种侵袭性非霍奇金淋巴瘤，常见于儿童和年轻人。ALCL 常携带染色体易位，导致癌蛋白核磷蛋白-间变性淋巴瘤激酶（NPM-ALK）的表达。NPM-ALK 触发淋巴瘤生长所需的关键下游分子事件仅部分揭示。在这里，我们发现在 NPM-ALK 触发的淋巴瘤发生的小鼠模型中，激活蛋白 1 家族成员 JUN 和 JUNB 通过转录调控血小板衍生生长因子受体-β（PDGFRB）促进淋巴瘤的发展和肿瘤的扩散。PDGFRB 的治疗性抑制显著延长了 NPM-ALK 转基因小鼠的存活时间，并增加了 ALK 特异性抑制剂在移植的 NPM-ALK 肿瘤中的疗效。值得注意的是，对一名难治性晚期 NPM-ALK(+) ALCL 患者进行 PDGFRA 和 PDGFRB 抑制导致快速、完全和持续缓解。总之，我们的数据将 PDGFRB 确定为以前未知的 JUN 和 JUNB 靶点，可能是治疗 ALCL 的一种非常有效的方法。
