Oncogenically active MYD88 mutations in human lymphoma.
Oncogenically active MYD88 mutations in human lymphoma.
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DOI：
10.1038/nature09671
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发表时间：
2011-02-03
期刊：
影响因子：
64.8
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
--
作者：
Ngo, Vu N.;Young, Ryan M.;Schmitz, Roland;Jhavar, Sameer;Xiao, Wenming;Lim, Kian-Huat;Kohlhammer, Holger;Xu, Weihong;Yang, Yandan;Zhao, Hong;Shaffer, Arthur L.;Romesser, Paul;Wright, George;Powell, John;Rosenwald, Andreas;Muller-Hermelink, Hans Konrad;Ott, German;Gascoyne, Randy D.;Connors, Joseph M.;Rimsza, Lisa M.;Campo, Elias;Jaffe, Elaine S.;Delabie, Jan;Smeland, Erlend B.;Fisher, Richard I.;Braziel, Rita M.;Tubbs, Raymond R.;Cook, J. R.;Weisenburger, Denny D.;Chan, Wing C.;Staudt, Louis M.
活化B细胞样（ABC）亚型弥漫性大B细胞淋巴瘤（DLBCL）仍然是这种恶性肿瘤的最难治愈的形式，尽管最近的治疗进展。在这些淋巴瘤中，组成性核因子（NF）-κB和JAK激酶信号传导促进恶性细胞存活，但这种信号传导的遗传基础尚不完全清楚。在这里，我们描述了ABC DLBCL对MYD 88的依赖性，MYD 88是一种介导Toll和白细胞介素（IL）-1受体信号传导的衔接蛋白，以及在ABC DLBCL肿瘤中发现影响MYD 88的高度复发性致癌突变。RNA干扰筛选显示MYD 88和相关激酶IRAK 1和IRAK 4对ABC DLBCL存活至关重要。高通量RNA重测序揭示了ABC DLBCL系中的MYD 88突变。值得注意的是，29%的ABC DLBCL肿瘤在MYD 88 Toll/IL-1受体（TIR）结构域的疏水核心中的进化不变残基处具有相同的氨基酸取代L265 P。这种突变在其他DLBCL亚型和伯基特淋巴瘤中罕见或不存在，但在9%的粘膜相关淋巴组织淋巴瘤中观察到。在较低的频率下，在MYD 88 TIR结构域中观察到额外的突变，发生在ABC和生发中心B细胞样（GCB）DLBCL亚型中。携带L265 P突变的ABC DLBCL细胞的存活由突变体而不是野生型MYD 88同种型维持，表明L265 P是功能获得性驱动突变。L265 P突变体通过自发组装含有IRAK 1和IRAK 4的蛋白质复合物来促进细胞存活，导致IRAK 4激酶活性、IRAK 1磷酸化、NF-κB信号传导、STAT 3的JAK激酶活化以及IL-6、IL-10和干扰素-β的分泌。因此，MYD 88信号通路是ABC DLBCL发病机制的组成部分，支持开发IRAK 4激酶和该通路其他组分的抑制剂，用于治疗携带致癌MYD 88突变的肿瘤。
The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, theMYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.
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影响因子：
16.8
作者：
Schmidlin H;Diehl SA;Blom B
通讯作者：
Blom B
影响因子：
4.8
作者：
Li, CS;Zienkiewicz, J;Hawiger, J
通讯作者：
Hawiger, J
影响因子：
56.9
作者：
Lenz, Georg;Davis, R. Eric;Staudt, Louis M.
通讯作者：
Staudt, Louis M.
影响因子：
2.7
作者：
Powers, JP;Li, SY;Wesche, H
通讯作者：
Wesche, H
TNFAIP3（A20）是霍奇金淋巴瘤和原发性纵隔B细胞淋巴瘤中的肿瘤抑制基因。
DOI：
10.1084/jem.20090528
发表时间：
2009-05-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Schmitz R;Hansmann ML;Bohle V;Martin-Subero JI;Hartmann S;Mechtersheimer G;Klapper W;Vater I;Giefing M;Gesk S;Stanelle J;Siebert R;Küppers R
通讯作者：
Küppers R