淋巴瘤中突变 IRF4 的转录重编程。
Transcriptional reprogramming by mutated IRF4 in lymphoma.
发表日期：2023 Nov 07
作者：
Nikolai Schleussner, Pierre Cauchy, Vedran Franke, Maciej Giefing, Oriol Fornes, Naveen Vankadari, Salam A Assi, Mariantonia Costanza, Marc A Weniger, Altuna Akalin, Ioannis Anagnostopoulos, Thomas Bukur, Marco G Casarotto, Frederik Damm, Oliver Daumke, Benjamin Edginton-White, J Christof M Gebhardt, Michael Grau, Stephan Grunwald, Martin-Leo Hansmann, Sylvia Hartmann, Lionel Huber, Eva Kärgel, Simone Lusatis, Daniel Noerenberg, Nadine Obier, Ulrich Pannicke, Anja Fischer, Anja Reisser, Andreas Rosenwald, Klaus Schwarz, Srinivasan Sundararaj, Andre Weilemann, Wiebke Winkler, Wendan Xu, Georg Lenz, Klaus Rajewsky, Wyeth W Wasserman, Peter N Cockerill, Claus Scheidereit, Reiner Siebert, Ralf Küppers, Rudolf Grosschedl, Martin Janz, Constanze Bonifer, Stephan Mathas
来源：
Experimental Hematology & Oncology
摘要：
编码转录因子 (TF) 的基因中的致病突变可能会影响 TF 与其同源 DNA 结合基序的相互作用。 TF 突变是否以及如何影响与 TF 复合元件 (CE) 的结合以及与其他 TF 的相互作用尚不清楚。在此，我们报告了 B 细胞身份受到干扰的人类淋巴瘤（特别是经典霍奇金淋巴瘤）中 TF 改变的独特机制。它是由反复出现的体细胞错义突变 c.295 T > C (p.Cys99Arg; p.C99R) 引起的，该突变针对干扰素调节因子 4 (IRF4) 的 DNA 结合结构域中心，干扰素调节因子 4 是免疫细胞中的关键 TF。 IRF4-C99R 从根本上改变了 IRF4 DNA 结合，失去了与规范 IRF 基序的结合，并获得了与规范和非规范 IRF CE 的新形态结合。 IRF4-C99R 通过阻断 IRF4 依赖性浆细胞诱导来彻底改变 IRF4 功能，并以非经典激活蛋白 1 (AP-1)-IRF-CE (AICE) 依赖性方式上调疾病特异性基因。我们的数据解释了单个突变如何导致 TF 特异性和基因调控的复杂转换，并为特异性阻断突变 TF 的新形态 DNA 结合活性开辟了视角。© 2023。作者。
Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.© 2023. The Author(s).