维也纳兽医大学、Ludwig Boltzmann癌症研究所和维也纳医科大学的研究人员,通过研究小鼠淋巴瘤模型发现,ALCL淋巴瘤的发展完全依赖于血小板源性生长因子B(PDGFRB),而研究显示这种蛋白与多种类型肿瘤的生长密切相关。

-2012年11月《自然-医学》

中文翻译


【题目】 PDGFR阻断是NPM-ALK驱动的淋巴瘤的常规有效疗法

【译文】间变性大细胞淋巴瘤(ALCL)是一种在儿童和年轻成年人中发现的侵袭性非何杰金氏淋巴瘤。ALCL通常携带有一种导致癌蛋白核磷蛋白-间变性淋巴瘤激酶(NPM-ALK)表达的染色体易位。NPM-ALK触发的淋巴瘤生长所必需的关键分子下游事件尚不清楚。本研究表明在NPM-ALK触发的淋巴瘤小鼠模型中,激活因子蛋白1家族成员JUN和JUNB通过血小板衍生生长因子β (PDGFRB)促进淋巴瘤发展和肿瘤传播。PDGFRB的抑制可以显著延长NPM-ALK转基因小鼠的生存期,并在移植的NPM-ALK肿瘤中增加ALK特异性抑制剂的效果。值得注意的是,在一个顽固性晚期NPM-ALK+ ALCL 患者中抑制PDGFRA和PDGFRB会导致症状快速、完整和持续的缓解。总之,我们的结果证实PDGFRB是先前未知的JUN和JUNB的靶点,它可能成为ALCL的高效疗法。

英文原稿


[Title]: PDGFR blockade is a rational and effective therapy for NPM-ALK–driven lymphomas

 [Authors]:Daniela Laimer,1, 25 Helmut Dolznig,2, 25 Karoline Kollmann,3, 25 Paul W Vesely,4, 24, 25 Michaela Schlederer,5 Olaf Merkel,6, 24 Ana-Iris Schiefer,1 Melanie R Hassler,1, 7 Susi Heider,1 Lena Amenitsch,1 Christiane Thallinger,7 ,21 Mangeng Cheng,21 Robert Eferl,22 Gerda Egger,1 Josef M Penninger,23 Ulrich Jaeger,13 Richard Moriggl,5 Giorgio Inghirami15, 19 & Lukas Kenner1, 5 et al.

[Abstract]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.      

原文地址

http://www.nature.com/nm/journal/v18/n11/abs/nm.2966.html

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